Mechanosensitive channels

Mechanosensitive channels, mechanosensitive ion channels or stretch-gated ion channels
 (not to be confused with mechanoreceptors). They are present in the membranes of organisms from the three domains of life: bacteria, archaea, and eukarya. They are the sensors for a number of systems including the senses of touch, hearing and balance, as well as participating in cardiovascular regulation and osmotic homeostasis (e.g. thirst). The channels vary in selectivity for the permeating ions from nonselective between anions and cations in bacteria, to cation selective allowing passage Ca2+, K+ and Na+ in eukaryotes, and highly selective K+ channels in bacteria and eukaryotes.
All organisms, and apparently all cell types, sense and respond to mechanical stimuli. MSCs function as mechanotransducers capable of generating both electrical and ion flux signals as a response to external or internal stimuli. Under extreme turgor in bacteria, non selective MSCs such as MSCL and MSCS serve as safety valves to prevent lysis. In specialized cells of the higher organisms, other types of MSCs are probably the basis of the senses of hearing and touch and sense the stress needed for muscular coordination. However, none of these channels have been cloned. MSCs also allow plants to distinguish up from down by sensing the force of gravity. MSCs are not pressure-sensitive, but sensitive to local stress, most likely tension in the surrounding lipid bilayer.
History.
Mechanosensitive channels were discovered in 1983 in the skeletal muscle of the chick by Falguni Guharay and Frederick Sachs. They were also observed (pub. 1986) in Xenopus oocytes, and frequently studied since that time.
Since then, MS channels have been found in cells from bacteria to humans: they are now known to be present in all three domains of life (Archaea, Bacteria and Eukarya, incl. plants and fungi). In the decades since the discovery of MS, the understanding of their structure and function has increased greatly, and several have been cloned. Specifically, the cloned eukaryotic mechanosensitive channels include the K+ selective 2P domain channels and the recently cloned cation selective PIEZO family.
Classification.
MS can be classified based on the type of ion to which they are permeable.
Cation Selective MSCs: As the name suggests, they exhibit a selective permeability for positive ions with the most selective channels being those for K+. The most common eukaryotic MSCs are cation selective passing Na+, K+ and Ca2+ but not Mg2+. They have a single channel conductance range (25-35 pS) and they are blocked by trivalent ion Gadolinium. The K+ selective MSCs such as TREK-1 are not blocked by Gd3+.
Anion Channels: they exhibit a significant permeability for negative ions, and are not predominant as cation MS. They have a large conductance range (> 300pS).
Non Selective ion channels: As the name indicates, they do not differentiate between positive and negative channels those are more common to Archaea and Bacteria, but rarely found in Eukarya.
Broadly, most MS can be classified as lipid-gated channels
Functions.
For a protein to be considered mechanosensitive, it must respond to a mechanical deformation of the membrane. Mechanical deformations can include changes in the tension, thickness, or curvature of the membrane. Mechanosensitive channels respond to membrane tension by altering their conformation between an open state and a closed state. One type of mechanically sensitive ion channel activates specialized sensory cells, such as cochlear hair cells and some touch sensory neurons, in response to forces applied to proteins.
Stretch-activated ion channels are of use in the initial formation of an action potential from a mechanical stimulus, for example by the mechanoreceptors in an animal's vibrissae (whiskers).
Afferent nerve fibers responsible for sensory stimulus detection and feedback are especially sensitive to stimulation. This results from the specialized mechanoreceptor cells that are superimposed upon the afferent nerve fibers. Stretch-activated ion channels are located on these mechanoreceptor cells and serve to lower the action potential threshold, thus making the afferent nerves more sensitive to stimulation. Afferent nerve endings without mechanoreceptor cells are called free nerve endings. They are less sensitive than the encapsulated afferent fibers and generally function in the perception of pain.
Stretch-activated ion channels are responsible for many bodily functions in mammals. In the skin they are responsible for sensing vibration, pressure sensation, stretch, touch, and light touch. They are expressed in sensory modalities including taste, hearing, smell, heat sensation, volume control, and vision. They can also regulate internal functions of our body including, but not limited to, osmotic pressure in cells, blood pressure in veins and arteries, micturition, and heart electrophysiology and contractility. In addition to these functionalities, stretch-activated ion channels have also been found to be involved with balance and proprioceptive sensation.
Channels that have traditionally been known as just “voltage-“ or “ligand-gated” have also been found to be mechanically sensitive as well. Channels exhibit mechanical sensitivity as a general property. However, mechanical stress affects various types of channels in different ways. Voltage and ligand gated channels can be modified slightly by mechanical stimulation, which might change their responsiveness or permeability slightly, but they still respond primarily to voltage or ligands, respectively.
Examples.
The different families of stretch-activated ion channels are responsible for different functions around the body. The DEG/ENaC family consists of two subgroups: the ENaC subfamily regulates Na+ reabsorption in kidney and lung epithelia; the ASIC subfamily is involved in fear conditioning, memory formation, and pain sensation. The TRP superfamily of channels are found in sensory receptor cells that are involved in heat sensation, taste, smell, touch, and osmotic and volume regulation. MscM, MscS, and MscL channels (mechanosensitive channels of mini, small, and large conductance) regulate osmotic pressure in cells by releasing intracellular fluid when they become too stretched. In the body, a possible role in myoblast development has been described. Furthermore, mechanically gated ion channels are also found in the stereocilia of the inner ear. Sound waves are able to bend the stereocilia and open up ion channels leading to the creation of nerve impulses. These channels also play a role in sensing vibration and pressure via activation of Pacinian corpuscles in the skin.
Transduction mechanisms.
There are two different types of stretch-activated channels between which it is important to distinguish: mechanically gated channels, which are directly influenced by mechanical deformations of the membrane, and mechanically sensitive channels, which are opened by second messengers released from the true mechanically gated channel.
Two different mechanisms have been found to open stretch-activated ion channels: Mechanical deformations in the cell membrane can increase the probability of the channels opening. Proteins of the extracellular matrix and cytoskeleton are tethered to extra - and intra-cytoplasmic domains, respectively, of the stretch-activated ion channels. Tension on these mechanosensory proteins causes these proteins to act as a signaling intermediate, resulting in the opening of the ion channel. All known stretch-activated ion channels in prokaryotic cells have been found to be opened by direct deformation of the lipid bilayer membrane. Channels that have been shown to exclusively use this mechanism of gating are the TREK-1 and TRAAK channels. In studies using mammalian hair cells, the mechanism that pulls on proteins tethered from the intra- and extra-cytoplasmic domain of the channel to the cytoskeleton and extracellular matrix, respectively, is the most likely model for ion channel opening.
Mechanical deformation of the cell membrane can be achieved by a number of experimental interventions, including magnetic actuation of nanoparticles. An example of this is the control of calcium influx of axons and boutons within neural networks.<ref name="doi:10.1021/acs.nanolett.6b04200">{cite journal |vauthors=Tay A, Dino DC | title = Magnetic Nanoparticle-Based Mechanical Stimulation for Restoration of Mechano-Sensitive Ion Channel Equilibrium in Neural Networks | journal = Nano Letters | volume = 17 | issue = 2 | pages = 886-892 | date = January 17 2017 | doi = 10.1021/acs.nanolett.6b04200 }}.</ref> Note that this is not an indication of 'magnetic stimulation' of mechanosensitive channels.
Gating mechanism.
Although MS vary in many aspects, structures and functions, all the MS studied to date share an important feature: in a process called "gating", they all open in a pore-like manner when protein channels are activated by a mechanical stimulus. There are currently two models of the gating process that explain how membrane-activated ion channels open.
Lipid bilayer Tension or stretch model: In this model tension in the lipid bilayer triggers conformational changes, thus leading to the opening of the channels. The tension perceived by the protein comes from the lipids. It has been demonstrated that the tension/stretch profile in the lipid bilayer is originated by membrane curvature and bilayer-protein hydrophobic mismatch.
Spring-like Tether model: In this model a spring-like tether is attached directly to the MS channel and can be present in either the cytoskeleton or the extracellular matrix linking these elements together. When external stimuli deflect the tether the displacement opens the channel. This particular mechanism has been demonstrated to be the responsible for gating hair cells which are responsible for hearing in vertebrates.
Bacterial MS.
Bacterial MS channels were first discovered by patch-clamp experiments in E. coli. They have been classified based on their conductance as mini (MscM), small (MscS) and large (MscL). These channels function in tandem-mode and are responsible of turgor regulation in bacteria; when activated by changes in the osmotic pressure. MscM is activated first at really low pressures followed by MscS, and finally MscL being the last chance of survival during osmotic shock. Their task was demonstrated when bacteria missing both MscS and MscL was lysed after exposure to osmotic downshocks.
MscS: Small conductance mechanosensitive channel.
The main conductance is 1nS in buffer solution. Channel-proteins have been found in gram positive and gram negative bacteria, archaea and plants. MscS channel was found after studies in "E. coli" spheroplasts. The identification of the gene family necessitated for MS of small conductance was as two different channels. YggB encoding MscS and KefA encoding MscK in "E. coli" further confirm its role osmotic regulation. Mutagenesis studies showed that when both genes YggB and KefA were deleted MscS lost its function, but maintain MscL and MscM, but mutants deficient of YggB and MscL showed that the function of those channel is to open in respond to pressure range right before cell rupture.
The 3D structure of this channel at closed state was elucidated after the crystallography study by Bass et al. which showed that at resolution of 3.9 Å this 31kDa protein is an homoheptamer forming a channel with 80 Å of diameter and 120 Å in length, each subunit contains three transmembrane domains (TM1, TM2, and TM3) with the N-terminal facing the periplasm and the C-terminal embedded in the cytoplasm. The TM3 is highly conserved in MscS family and it is thought to play an important role in MS prokaryotic gating. MscS is a small protein composed of 286 amino acid residues activated by both tension in the lipid bilayer and voltage; in 2002 Vasquez et al. detailed this process and showed that during the change from closed state to open state the TM1 tilt and rotate making TM2 being exposed to the membrane and the TM3 helices expand, tilt, and rotate. During the rearrangement the confined part of the pore was measured as 11 Å, and water molecules were more accessible to the TM3. The two transmembrane domains are in continuous contact with the lipid bilayer and are thought to be the sensor for the tension in the lipid bilayer as well as sensor for voltage because of the three arginine residues present in those domains.
Although MscS is activated by voltage it has been demonstrated that, voltage itself is insufficient to open the channel, thus functioning in a cooperative manner with the channel. The more positive voltage, the higher the probabilities of opening the channel as long as pressure over the threshold is still applied in the system; the performance of this channel at higher voltage has not been completely understood. MscS has a small affinity for negative ions including Cl-, and glutamate.
MscL: Large conductance mechanosensitive channel.
In bacteria MscL was the first MS channels cloned and sequenced, and is by far one of the most studied channels. The gene encoding MscL protein is trkA and it is located in the inner membrane of the "E. coli". The protein is 17 KDa, and consists of 136 amino acids; mostly hydrophobic residues resulting in two hydrophobic segments, however molecular weight of the functional channel is presumed to be 60-70 KDa from gel filtration experiments, suggesting oligomerization. As a common feature no cysteines residues are present in this channel.
In 1998 the homolog MscL from mycobacterium tuberculosis Tb-MscL was elucidated at closed state by X ray crystallography at 3.5 Å resolution. The protein is a homopentamer composed mostly of helical regions trans orientation of the helices with respect to the bilayer, with two domains: the cytoplasmic and the transmembrane. The channel is 85 Å in length, 35 Å and 50 Å for the cytoplasmic transmembrane domain respectively and 50 Å in diameter. The helices cross the membrane twice with both the C-terminal and the N-terminal, thus having two transmembrane domains TM1 and TM2 being TM1 the most conserved region among MscL proteins especially at the N-terminal region. It is located in the cytoplasm and forms a α-hydrophobic helix called S1; the region between the transmembrane domains form a loop that is divided into two regions: S2 a glycine-proline rich region and S3 a short helical section. The secondary structure of the protein is resistant to thermal denaturation still in the presence of SDS.
During the activation of the prokaryotic MscL by tension in the lipid bilayer an intermediate state was determined. The S1 segments form a bundle when the structure is in the closed state, and the crosslinking of S1 segments prevents the opening of the channel. When tension is applied to the membrane the transmembrane barrel-like structure expand and stretch apart the region S1-TM1 allowing the channel to open. The size of the pore at open state is approximately 25Å. The transition from closed to intermediate state is accompanied by small movements of the TM1; further transitions to the open stated are characterized by big rearrangements in both the TM1 and TM2.
Role of lipid bilayer in MS.
The lipid bilayer is an important structure in all living cells; it has many functions such as separation of compartments, and signaling among others. In the case of the prokaryotic protein channels MscS and MscL both are gated by tension in the lipid bilayer, thus suggesting an important role in such a complex structures.
The tension in the membrane bilayer has been extensively studied, simple intrinsic properties of the lipids can account for the contributions in the free energy of the open, intermediate, and close state of the MS channels. The bilayer possess different features that allows it to transduce tension and to prevent exhaustive deformations, the first one is “in plane fluidity of the lipid bilayer” meaning that any in plane tension in the lipid bilayer is felt homogenously in the absence of cytoskeleton interactions. The lipid molecules have specific spaces, preventing the bilayer from changing.
The contribution of membrane deformation in the gating of MS channels can be divided in two types: the deformation of the plane of the bilayer, and the deformation of the thickness of the bilayer. Also during any process involving changes in the structure, the free energy of the process itself is also an important factor. During gating the major processes that account for this event are: hydrophobic mismatch, and membrane curvature. It has been calculated that the free energy of the tension in the lipid bilayer is similar to the energy needed for gating the channels.
A different study showed that the length of the hydrophobic tail affects its functioning as well as supporting the different states, Phosphatidylcholine (PC) 18 stabilizes better the open state of the MscL channel, PC 14 stabilizes the intermediate state, and a mixture of PC 18 and lysophosphatidylcholine (LPC) stabilizes the closed state, suggesting that the bilayer thickness (for carbon tail lengths of 16, 18 and 20) affects channel function. In conclusion the energy from the environment of the membrane plays an important role in the total energy of channel gating.
Eukaryotes.
In eukaryotes, two of the best known mechanosensitive ion channels are the potassium channels TREK-1 and TRAAK, both of which are found in mammalian neurons.
Recently, a new mechanosensitive ion channel family was cloned, with two mammalian members, PIEZO1 and PIEZO2. Both these channels are expressed in the lungs and bladder, organs with important mechanosensory functions. Piezo1 is also expressed in the skin, and in red blood cells, and its gain of function mutations cause hereditary xerocytosis. Piezo2 is expressed in sensory neurons of the dorsal root and trigeminal ganglia indicating that it may play a role in touch sensation. Mutations in piezo2 are associated with a human disease named Distal Arthrogryposis.
Physiological role of MS.
MS channels are ubiquitously expressed in the membrane of prokaryotes suggesting their significance. In Bacteria and Archaea the function of these channels is conserved and it has been demonstrated that they play a role in turgor regulation. In Eukarya MS channels are involved in all five senses. The main family is TRP, and one good example is hair cells involved in the hearing process. When a wave of sound deflects the stereocilia, the channel opens. This is an instance of the Spring-like Tether gating mechanism. Recent studies have revealed a new role of mechanosensitive pathways in which naive mesenchymal stem cells are committed to a particular lineage based on the elasticity of its surrounding matrix.
MS have also been suggested as a potential target for antibiotics, the reasoning behind this idea is that both McsS and MscL are highly conserved among prokaryotes, but their homologs have not been found in animals making them an exceptional potential for further studies.
In mammalian neurons, opening of the ion channels depolarizes the afferent neuron producing an action potential with sufficient depolarization. Channels open in response to two different mechanisms: the prokaryotic model and the mammalian hair cell model. Stretch-activated ion channels have been shown to detect vibration, pressure, stretch, touch, sounds, tastes, smell, heat, volume, and vision. Stretch-activated ion channels have been categorized into three distinct "superfamilies": the ENaC/DEG family, the TRP family, and the K1 selective family. These channels are involved with bodily functions such as blood pressure regulation. They are shown to be associated with many cardiovascular diseases. Stretch-activated channels were first observed in chick skeletal muscles by Falguni Guharay and Frederick Sachs in 1983 and the results were published in 1984. Since then stretch-activated channels have been found in cells from bacteria to humans as well as plants.
The opening of these channels is central to a neuron's response to pressure, often osmotic pressure and blood pressure, to regulate ionic flow in internal environments.
Techniques used to study MS.
This is a short list of the most frequently techniques used to study the properties, function, mechanism and other features of these channels:
Through experiments performed on the cytoskeleton and extra-cytoplasmic matrix of stretch-activated ion channels, these structures have been shown to play significant roles in mechanotransduction. In one such experiment on adult heart cells, whole cell recordings were taken on cells being squeezed with two pipettes at 1 Hz/1 um. This squeezing produced no current until five minutes in when a large depolarization was observed. Hereafter, the cell became extremely responsive to every compression and gradually decreased sensitivity over the next few minutes. Researchers hypothesized that, initially, the cytoskeleton was buffering the mechanical deformation of the squeezing from the channel. The depolarization at five minutes was the cytoskeleton snapping which subsequently caused the channel to sense the mechanical deformations and thereby respond to the stimuli. Researchers believe that over the few minutes where the channel repaired itself the cytoskeleton must be repairing itself and newly adapting to the squeezing stimuli.
Structure.
ENaC/DEG superfamily.
ASIC.
There are six known ASIC subunits, ASIC1a, ASIC1b, ASIC2a, ASIC2b, ASIC3, and ASIC4, which have two transmembrane domains, extracellular and intracellular loops, and C and N termini. These ASIC subunits likely form tetramers with varying kinetics, pH sensitivity, tissue distribution, and pharmacological properties.
TRP superfamily.
There are seven subfamilies within the TRP superfamily: TRPC (canonical), TRPV (vanilloid), TRPM (melastatin), TRPP (polycystin), TRPML (mucolipin), TRPA (ankyrin), and TRPN (NOMPC-like). TRP proteins typically consist of six transmembrane domains, S1, S2, S3, S4, S5, and S6, with a pore between S5 and S6. These contain intracellular N and C termini, which form tetramers and vary in length and domain. Within the channel there are ankyrins, which are structural proteins that mediate protein-protein interactions, and are thought to contribute to the tether model of stretch-activated channel opening. NOMPC, identified in D. melanogaster mechanotransduction and a member of the TRPN subfamily, contains a relatively high number of ankyrins.
K1-selective superfamily.
K2P channels consist of six subfamilies and contain four transmembrane domains, which form two pores each between domains 1–2 and 3–4. K2P channels also contain a short N terminal domain and a C terminal which varies in length. There is also a large extracellular linker region between domain 1 and the first pore formed between domains 1–2.
Examples.
TRP channels are typically non-selective, although a few are selective for calcium or hydrated magnesium ions, and are composed of integral membrane proteins. Although many TRP channels are activated by voltage change, ligand binding, or temperature change, some TRP channels have been hypothesized to be involved in mechanotransduction. Some examples are TRPV4, which mediates mechanical load in a variety of tissues, including the liver, heart, lung, trachea, testis, spleen, salivary glands, cochlea, and vascular endothelial cells, as well as TRPC1 and TRPC6, which are involved in muscle mechanosensation. TRPC1 is expressed in the myocytes of the heart, arteries, and skeletal muscle. TRPC1 is widely considered to be a non-selective “store-operated ion channel” (SOC) involved in the calcium influx following calcium depletion of the endoplasmic reticulum of the cell. TRPC6 is a calcium-permeable non-selective cation channel expressed in the cardiovascular system. TRPC6 is potentially a sensor of mechanically and osmotically induced membrane stretch, and is possibly directly gated by membrane tension. Other examples include TREK-1 and TRAAK which are found in mammalian neurons and are classified as potassium channels in the tandem pore domain class and "MID-1" (also known as "MCLC" or CLCC1.)
The six K2P channel subfamilies are regulated by various physical, cellular, and pharmacological stimulants, including membrane stretch, heat, pH change, calcium flux, and protein kinases.
Clinical relevance.
Stretch-activated ion channels perform important functions in many different areas of our body. Pressure-dependent myogenic constriction resistance arteries require these channels for regulation in the smooth muscle of the arteries. They have been found to be used for volume sensing in animals and blood pressure regulation. Bacteria have been shown to relieve hydrostatic pressure through MscL and MscS channels.
Pathologies associated with stretch-activated ion channels.
Stretch-activated ion channels have been correlated with major pathologies. Some of these pathologies include cardiac arrhythmia (such as atrial fibrillation), cardiac hypertrophy, Duchenne muscular dystrophy, and other cardiovascular diseases.
Blocking stretch-activated ion channels.
Gadolinium (Gd3+) and other lanthanides have been shown to block stretch-activated ion channel function. The peptide toxin isolated from the Chilean rose tarantula (Grammostola spatulata), mechanotoxin 4 (GsMTx4) has been shown to inhibit these channels from the extracellular side, but it does not inhibit all stretch-activated ion channels and particularly has no effect on 2p channels.
List of diseases associated with mechanosensitive channels.
Abnormalities in the function of MS channels can cause:
References.
The following is not referenced in the article, and/or is in conflict with Engler, A. et al., 2006:


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Nuclear receptor

In the field of molecular biology, nuclear receptors are a class of proteins found within cells that are responsible for sensing steroid and thyroid hormones and certain other molecules. In response, these receptors work with other proteins to regulate the expression of specific genes, thereby controlling the development, homeostasis, and metabolism of the organism.
Nuclear receptors have the ability to directly bind to DNA and regulate the expression of adjacent genes; hence these receptors are classified as transcription factors. The regulation of gene expression by nuclear receptors generally only happens when a ligand—a molecule that affects the receptor's behavior—is present. More specifically, ligand binding to a nuclear receptor results in a conformational change in the receptor, which, in turn, activates the receptor, resulting in up- or down-regulation of gene expression.
A unique property of nuclear receptors that differentiates them from other classes of receptors is their ability to directly interact with and control the expression of genomic DNA. As a consequence, nuclear receptors play key roles in both embryonic development and adult homeostasis. As discussed below, nuclear receptors may be classified according to either mechanism or homology.
Species distribution.
Nuclear receptors are specific to metazoans (animals) and are not found in protists, algae, fungi, or plants. Amongst the early-branching animal lineages with sequenced genomes, two have been reported from the sponge "Amphimedon queenslandica", two from the ctenophore "Mnemiopsis leidyi" four from the placozoan "Trichoplax adhaerens" and 17 from the cnidarian "Nematostella vectensis". There are 270 nuclear receptors in the nematode "C. elegans" alone, 21 in "D. melanogaster" and other insects, 73 in zebrafish. Humans, mice, and rats have respectively 48, 49, and 47 nuclear receptors each.
Ligands.
Ligands that bind to and activate nuclear receptors include lipophilic substances such as endogenous hormones, vitamins A and D, and xenobiotic endocrine disruptors. Because the expression of a large number of genes is regulated by nuclear receptors, ligands that activate these receptors can have profound effects on the organism. Many of these regulated genes are associated with various diseases, which explains why the molecular targets of approximately 13% of U.S. Food and Drug Administration (FDA) approved drugs target nuclear receptors.
A number of nuclear receptors, referred to as orphan receptors, have no known (or at least generally agreed upon) endogenous ligands. Some of these receptors such as FXR, LXR, and PPAR bind a number of metabolic intermediates such as fatty acids, bile acids and/or sterols with relatively low affinity. These receptors hence may function as metabolic sensors. Other nuclear receptors, such as CAR and PXR appear to function as xenobiotic sensors up-regulating the expression of cytochrome P450 enzymes that metabolize these xenobiotics.
Structure.
Most nuclear receptors have molecular masses between 50,000 and 100,000 daltons.
Nuclear receptors are modular in structure and contain the following domains:
The N-terminal (A/B), DNA-binding (C), and ligand binding (E) domains are independently well folded and structurally stable while the hinge region (D) and optional C-terminal (F) domains may be conformationally flexible and disordered. Domains relative orientations are very different by comparing three known multi-domain crystal structures, two of them binding on DR1 (DBDs separated by 1 bp), one binding on DR4 (by 4 bp).
Mechanism of action.
Nuclear receptors are multifunctional proteins that transduce signals of their cognate ligands. Nuclear receptors (NRs) may be classified into two broad classes according to their mechanism of action and subcellular distribution in the absence of ligand.
Small lipophilic substances such as natural hormones diffuse through the cell membrane and bind to nuclear receptors located in the cytosol (type I NR) or nucleus (type II NR) of the cell. Binding causes a conformational change in the receptor which, depending on the class of receptor, triggers a cascade of downstream events that direct the NRs to DNA transcription regulation sites which result in up or down-regulation of gene expression. They generally function as homo/heterodimers. In addition, two additional classes, type III which are a variant of type I, and type IV that bind DNA as monomers have also been identified.
Accordingly, nuclear receptors may be subdivided into the following four mechanistic classes:
Type I.
Ligand binding to type I nuclear receptors in the cytosol results in the dissociation of heat shock proteins, homo-dimerization, translocation ("i.e.", active transport) from the cytoplasm into the cell nucleus, and binding to specific sequences of DNA known as hormone response elements (HREs). Type I nuclear receptors bind to HREs consisting of two half-sites separated by a variable length of DNA, and the second half-site has a sequence inverted from the first (inverted repeat). Type I nuclear receptors include members of subfamily 3, such as the androgen receptor, estrogen receptors, glucocorticoid receptor, and progesterone receptor.
It has been noted that some of the NR subfamily 2 nuclear receptors may bind to direct repeat instead of inverted repeat HREs. In addition, some nuclear receptors that bind either as monomers or dimers, with only a single DNA binding domain of the receptor attaching to a single half site HRE. These nuclear receptors are considered orphan receptors, as their endogenous ligands are still unknown.
The nuclear receptor/DNA complex then recruits other proteins that transcribe DNA downstream from the HRE into messenger RNA and eventually protein, which causes a change in cell function.
Type II.
Type II receptors, in contrast to type I, are retained in the nucleus regardless of the ligand binding status and in addition bind as hetero-dimers (usually with RXR) to DNA. In the absence of ligand, type II nuclear receptors are often complexed with corepressor proteins. Ligand binding to the nuclear receptor causes dissociation of corepressor and recruitment of coactivator proteins. Additional proteins including RNA polymerase are then recruited to the NR/DNA complex that transcribe DNA into messenger RNA.
Type II nuclear receptors include principally subfamily 1, for example the retinoic acid receptor, retinoid X receptor and thyroid hormone receptor.
Type III.
Type III nuclear receptors (principally NR subfamily 2) are similar to type I receptors in that both classes bind to DNA as homodimers. However, type III nuclear receptors, in contrast to type I, bind to direct repeat instead of inverted repeat HREs.
Type IV.
Type IV nuclear receptors bind either as monomers or dimers, but only a single DNA binding domain of the receptor binds to a single half site HRE. Examples of type IV receptors are found in most of the NR subfamilies.
Dimerization.
Human Nuclear Receptors are capable of dimerizing with many other Nuclear Receptors (homotypic dimerization), as has been shown from large-scale Y2H experiments and text mining efforts of the literature that were focused on specific interactions. Nevertheless, there exists specificity, with members of the same subfamily having very similar NR dimerization partners and the underlying dimerization network has certain topological features, such as the presence of highly connected hubs (RXR and SHP).
Coregulatory proteins.
Nuclear receptors bound to hormone response elements recruit a significant number of other proteins (referred to as transcription coregulators) that facilitate or inhibit the transcription of the associated target gene into mRNA. The function of these coregulators are varied and include chromatin remodeling (making the target gene either more or less accessible to transcription) or a bridging function to stabilize the binding of other coregulatory proteins. Nuclear receptors may bind specifically to a number of coregulator proteins, and thereby influence cellular mechanisms of signal transduction both directly, as well as indirectly.
Coactivators.
Binding of agonist ligands (see section below) to nuclear receptors induces a conformation of the receptor that preferentially binds coactivator proteins. These proteins often have an intrinsic histone acetyltransferase (HAT) activity, which weakens the association of histones to DNA, and therefore promotes gene transcription.
Corepressors.
Binding of antagonist ligands to nuclear receptors in contrast induces a conformation of the receptor that preferentially binds corepressor proteins. These proteins, in turn, recruit histone deacetylases (HDACs), which strengthens the association of histones to DNA, and therefore represses gene transcription.
Agonism vs antagonism.
Depending on the receptor involved, the chemical structure of the ligand and the tissue that is being affected, nuclear receptor ligands may display dramatically diverse effects ranging in a spectrum from agonism to antagonism to inverse agonism.
Agonists.
The activity of endogenous ligands (such as the hormones estradiol and testosterone) when bound to their cognate nuclear receptors is normally to upregulate gene expression. This stimulation of gene expression by the ligand is referred to as an agonist response. The agonistic effects of endogenous hormones can also be mimicked by certain synthetic ligands, for example, the glucocorticoid receptor anti-inflammatory drug dexamethasone. Agonist ligands work by inducing a conformation of the receptor which favors coactivator binding (see upper half of the figure to the right).
Antagonists.
Other synthetic nuclear receptor ligands have no apparent effect on gene transcription in the absence of endogenous ligand. However they block the effect of agonist through competitive binding to the same binding site in the nuclear receptor. These ligands are referred to as antagonists. An example of antagonistic nuclear receptor drug is mifepristone which binds to the glucocorticoid and progesterone receptors and therefore blocks the activity of the endogenous hormones cortisol and progesterone respectively. Antagonist ligands work by inducing a conformation of the receptor which prevents coactivator and promotes corepressor binding (see lower half of the figure to the right).
Inverse agonists.
Finally, some nuclear receptors promote a low level of gene transcription in the absence of agonists (also referred to as basal or constitutive activity). Synthetic ligands which reduce this basal level of activity in nuclear receptors are known as inverse agonists.
Selective receptor modulators.
A number of drugs that work through nuclear receptors display an agonist response in some tissues and an antagonistic response in other tissues. This behavior may have substantial benefits since it may allow retaining the desired beneficial therapeutic effects of a drug while minimizing undesirable side effects. Drugs with this mixed agonist/antagonist profile of action are referred to as selective receptor modulators (SRMs). Examples include Selective Androgen Receptor Modulators (SARMs), Selective Estrogen Receptor Modulators (SERMs) and Selective Progesterone Receptor Modulators (SPRMs). The mechanism of action of SRMs may vary depending on the chemical structure of the ligand and the receptor involved, however it is thought that many SRMs work by promoting a conformation of the receptor that is closely balanced between agonism and antagonism. In tissues where the concentration of coactivator proteins is higher than corepressors, the equilibrium is shifted in the agonist direction. Conversely in tissues where corepressors dominate, the ligand behaves as an antagonist.
Alternative mechanisms.
Transrepression.
The most common mechanism of nuclear receptor action involves direct binding of the nuclear receptor to a DNA hormone response element. This mechanism is referred to as transactivation. However some nuclear receptors not only have the ability to directly bind to DNA, but also to other transcription factors. This binding often results in deactivation of the second transcription factor in a process known as transrepression. One example of a nuclear receptor that are able to transrepress is the glucocorticoid receptor (GR). Furthermore, certain GR ligands known as Selective Glucocorticoid Receptor Agonists (SEGRAs) are able to activate GR in such a way that GR more strongly transrepresses than transactivates. This selectivity increases the separation between the desired antiinflammatory effects and undesired metabolic side effects of these selective glucocorticoids.
Non-genomic.
The classical direct effects of nuclear receptors on gene regulation normally take hours before a functional effect is seen in cells because of the large number of intermediate steps between nuclear receptor activation and changes in protein expression levels. However it has been observed that many effects of the application of nuclear hormones, such as changes in ion channel activity, occur within minutes which is inconsistent with the classical mechanism of nuclear receptor action. While the molecular target for these non-genomic effects of nuclear receptors has not been conclusively demonstrated, it has been hypothesized that there are variants of nuclear receptors which are membrane associated instead of being localized in the cytosol or nucleus. Furthermore, these membrane associated receptors function through alternative signal transduction mechanisms not involving gene regulation.
While it has been hypothesized that there are several membrane associated receptors for nuclear hormones, many of the rapid effects have been shown to require canonical nuclear receptors. However, testing the relative importance of the genomic and nongenomic mechanisms in vivo has been prevented by the absence of specific molecular mechanisms for the nongenomic effects that could be blocked by mutation of the receptor without disrupting its direct effects on gene expression.
A molecular mechanism for non-genomic signaling through the nuclear thyroid hormone receptor TRβ involves the phosphatidylinositol 3-kinase (PI3K). This signaling can be blocked by a single tyrosine to phenylalanine substitution in TRβ without disrupting direct gene regulation. When mice were created with this single, conservative amino acid substitution in TRβ, synaptic maturation and plasticity in the hippocampus was impaired almost as effectively as completely blocking thyroid hormone synthesis. This mechanism appears to be conserved in all mammals but not in TRα or any other nuclear receptors. Thus, phosphotyrosine-dependent association of TRβ with PI3K provides a potential mechanism for integrating regulation of development and metabolism by thyroid hormone and receptor tyrosine kinases. In addition, thyroid hormone signaling through PI3K can alter gene expression.
Family members.
The following is a list of the 48 known human nuclear receptors (and their orthologs in other species) categorized according to sequence homology. The list also includes selected family members that lack human orthologs (NRNC symbol highlighted in yellow).
Of the two 0-families, 0A has a family 1-like DBD, and 0B has a very unique LBD. The second DBD of family 7 is probably related to the family 1 DBD. Three probably family-1 NRs from "Biomphalaria glabrata" possess a DBD along with an family 0B-like LBD. The placement of "C. elegans" nhr-1 () is disputed: although most sources place it as NR1K1, manual annotation at WormBase considers it a member of NR2A. There used to be a group 2D for which the only member was "Drosophilia" HR78/NR1D1 () and orthologues, but it was merged into group 2C later due to high similarity, forming a "group 2C/D". Knockout studies on mice and fruit flies support such a merged group.
Evolution.
A topic of debate has been on the identity of the ancestral nuclear receptor as either a ligand-binding or an orphan receptor. This debate began more than twenty-five years ago when the first ligands were identified as mammalian steroid and thyroid hormones. Shortly thereafter, the identification of the ecdysone receptor in Drosophila introduced the idea that nuclear receptors were hormonal receptors that bind ligands with a nanomolar affinity. At the time, the three known nuclear receptor ligands were steroids, retinoids, and thyroid hormone, and of those three, both steroids and retinoids were products of terpenoid metabolism. Thus, it was postulated that ancestral receptor would have been liganded by a terpenoid molecule.
In 1992, a comparison of the DNA-binding domain of all known nuclear receptors led to the construction of a phylogenic tree of nuclear receptor that indicated that all nuclear receptors shared a common ancestor. As a result, there was an increased effort upon uncovering the state of the first nuclear receptor, and by 1997 an alternative hypothesis was suggested: the ancestral nuclear receptor was an orphan receptor and it acquired ligand-binding ability over time This hypothesis was proposed based on the following arguments:
Over the next 10 years, experiments were conducted to test this hypothesis and counterarguments soon emerged:
A combination of this recent evidence, as well as an in-depth study of the physical structure of the nuclear receptor ligand binding domain has led to the emergence of a new hypothesis regarding the ancestral state of the nuclear receptor. This hypothesis suggests that the ancestral receptor may act as a lipid sensor with an ability to bind, albeit rather weakly, several different hydrophobic molecules such as, retinoids, steroids, hemes, and fatty acids. With its ability to interact with a variety of compounds, this receptor, through duplications, would either lose its ability for ligand-dependent activity, or specialize into a highly specific receptor for a particular molecule.
History.
Below is a brief selection of key events in the history of nuclear receptor research.


Ammonium cyanide

Ammonium cyanide is an unstable inorganic compound with the formula NH4CN.
Uses.
Ammonium cyanide is generally used in organic synthesis. Being unstable, it is not shipped or sold commercially.
Preparation.
Ammonium cyanide is prepared in solution by bubbling hydrogen cyanide into aqueous ammonia at a low temperature
It may be prepared by the reaction of calcium cyanide and ammonium carbonate:
In dry state, ammonium cyanide is made by heating a mixture of potassium cyanide or potassium ferrocyanide with ammonium chloride and condensing the vapours into ammonium cyanide crystals:
Reactions.
Ammonium cyanide decomposes to ammonia and hydrogen cyanide, often forming a black polymer of hydrogen cyanide:
It undergoes double decomposition reactions in solution with a number of metal salts.
It reacts with glyoxal, producing glycine (aminoacetic acid):
Reactions with ketones yield aminonitriles, as in the first step of the Strecker amino acid synthesis:
Toxicity.
The solid or its solution is highly toxic. Ingestion can cause death. Exposure to the solid can be harmful as it decomposes to highly toxic hydrogen cyanide and ammonia.
Chemical analysis.
Ammonium cyanide may be analyzed by heating the salt and trapping the decomposed products: hydrogen cyanide and ammonia in water at low temperatures. The aqueous solution is analyzed for cyanide ion by silver nitrate titrimetric method or an ion-selective
electrode method, and ammonia is measured by titration or electrode technique.


Elephant shrew

Elephant shrews, also called jumping shrews or sengis, are small insectivorous mammals native to Africa, belonging to the family Macroscelididae, in the order Macroscelidea. Their traditional common English name "elephant shrew" comes from a perceived resemblance between their long noses and the trunk of an elephant, and their superficial similarity with shrews (family Soricidae) in the order Eulipotyphla. However, phylogenetic analysis revealed that elephant shrews are not classified with true shrews, but are in fact more closely related to elephants than shrews. In 1997, the biologist Jonathan Kingdon proposed that they instead be called "sengis" (singular "sengi"), a term derived from the Bantu languages of Africa, and in 1998, they were classified into the new clade Afrotheria.
They are widely distributed across the southern part of Africa, and although common nowhere, can be found in almost any type of habitat, from the Namib Desert to boulder-strewn outcrops in South Africa to thick forest. One species, the North African elephant shrew, remains in the semiarid, mountainous country in the far northwest of the continent. The Somali elephant shrew went missing from 1968 to 2020 but was rediscovered by a group of scientists in Djibouti.
Characteristics.
The creature is one of the fastest small mammals, having been recorded to reach speeds of . Compared to other mammalian insectivores, sengis have relatively large brains.
Elephant shrews are small, quadrupedal, insectivorous mammals resembling rodents or opossums, with scaly tails, long snouts, and legs quite long for their size, which are used to move from one place to another like rabbits. They vary in size from about , from . The short-eared elephant shrew has an average size of . Although the size of the trunk varies among species, all are able to twist it about in search of food. Their lifespans are about two and a half to four years in the wild. They have large canine teeth, and also high-crowned cheek teeth similar to those of ungulates. Their dental formula is G
Although mostly diurnal and very active, they are difficult to trap and very seldom seen; elephant shrews are wary, well camouflaged, and adept at dashing away from threats. Several species make a series of cleared pathways through the undergrowth and spend their day patrolling them for insect life. If the animal is disturbed, the pathway provides an obstacle-free escape route.
Elephant shrews are not highly social animals, but many live in monogamous pairs, which share and defend their home territory, marked using scent glands. "Rhynchocyon" species also dig small conical holes in the soil, bandicoot-style, but others may make use of natural crevices, or make leaf nests.
Short-eared elephant shrews inhabit the dry steppes and stone deserts of southwestern Africa. They can even be found in the Namib Desert, one of the driest regions of the earth. Females drive away other females, while males try to ward off other males. Although they live in pairs, the partners do not care much for each other and their sole purpose of even associating with the opposite sex is for reproduction. Social behaviors are not very common and they even have separate nests. The one or two young are well developed at birth; they are able to run within a few hours.
Female elephant shrews undergo a menstrual cycle similar to that of human females and the species is one of the few nonprimate mammals to do so. Elephant shrews were used in the 1940s to study the human menstruation cycle. The elephant shrew mating period lasts for several days. After mating, the pair will return to their solitary habits. After a gestation period varying from 45 to 60 days, the female will bear litters of one to three young several times a year. The young are born relatively well developed, but remain in the nest for several days before venturing outside.
After five days, the young's milk diet is supplemented with mashed insects, which are collected and transported in the cheek pouches of the female. The young then slowly start to explore their environment and hunt for insects. After about 15 days, the young will begin the migratory phase of their lives, which lessens their dependency on their mother. The young will then establish their own home ranges (about ) and will become sexually active within 41–46 days.
The thermal characteristics of elephant shrews with similar body size, habitat and distribution are very close in most of the classifications. They can maintain homeothermy in different ambient temperatures where most of the species regulate their body temperature at 35 °C and neither become hyperthermic but they balance the heat offload by increasing the EWL (evaporative water loss).
Feeding habits.
Elephant shrews mainly eat insects, spiders, centipedes, millipedes, and earthworms. An elephant shrew uses its nose to find prey and uses its tongue to flick small food into its mouth, much like an anteater. Eating large prey can pose a challenge; an elephant shrew struggling with an earthworm must first pin its prey to the ground with a forefoot. Then, turning its head to one side, it chews pieces off with its cheek teeth, much like a dog chewing a bone. This is a sloppy process, and many small pieces of worm drop to the ground; these are simply flicked up with the tongue. Some elephant shrews also feed on small amounts of plant matter, especially new leaves, seeds, and small fruits.
Evolution.
A number of fossil species are known, all from Africa. They were separate from the similar-appearing order Leptictida. A considerable diversification of macroscelids occurred in the Paleogene period. Some, such as "Myohyrax", were so similar to hyraxes that they were initially included with that group, while others, such as "Mylomygale", were relatively rodent-like. These unusual forms all died out by the Pleistocene. Although macroscelids were classified in the past with many groups, often on the basis of superficial characteristics, considerable morphological and molecular evidence places them within Afrotheria, at the base of Afroinsectivora.
In terms of timing, the divergence between macroscelids and afrosoricidans is thought to have occurred roughly 57.5 million years (Ma) ago, in the late Paleocene, while the diversification of extant macroscelids apparently began when the "Rhynchocyon" lineage split off about 33 Ma ago, in the early Oligocene. "Elephantulus" is considered to have separated from Macroscelidini later in the Oligocene, about 28.5 Ma ago.
Classification.
The 20 species of elephant shrew are placed in six genera, three of which are monotypic:


Anna Macleod

Anna MacGillivray Macleod DSc (15 May 1917 – 13 August 2004) was a Scottish biochemist and academic, an authority on brewing and distilling. She was a professor at Heriot-Watt University in Edinburgh. She was the world's first female Professor of Brewing and Biochemistry.
Family.
Born in Kirkhill, she was the daughter of Margaret Ingram Sangster and Rev. Alasdair MacGillivray Macleod. Her family lineage traces to the Isle of Lewis, where her grandfather, Rev. George Macleod, was the Minister of Garrabost. Her father was born on the Isle of Lewis. She was second cousin to politician and former Chancellor of the Exchequer, Iain Norman Macleod. Her family belongs to the branch of the Macleods of Pabbay and Uig.
Her father, who was a Minister of the Church, died at an early age. He and her mother were both in 1914 graduates of Aberdeen University. Her two brothers were both doctors of medicine: her elder brother was John George Macleod, editor of "Davidson's Textbook of Medicine" and the author of "Clinical Examination", and her younger brother was Alasdair MacGillivray Macleod, a general practitioner in Linlithgow.
Education and profession.
Macleod was educated at Invergordon Academy and Edinburgh Ladies' College. In 1939 she graduated from University of Edinburgh with a BSc with honours in botany. She joined the faculty of Heriot-Watt University in 1945, where she remained until her retirement in 1977. She returned in 1951 to the University of Edinburgh to study for her PhD. In the late 1960s, she was awarded a Doctor of Science, from the University, for a thesis on the germination of barley.
In 1961, together with Leslie Samuel Cobley, she co-edited "Contemporary Botanical Thought", published by Oliver and Boyd. She edited the "Journal of the Institute of Brewing" from 1964 to 1976, and she was the first female President of that organisation (now the Institute of Brewing and Distilling), from 1970 to 1972. In 1975, she was appointed Professor of Brewing at Heriot-Watt University. In 1976, she was the recipient of the Horace Brown medal. She retired in 1977, as professor emeritus.
In 1993, Heriot-Watt University awarded her an honorary Doctorate of Science for her discovery of gibberellic acid, which was an advantage for the maltsters, as it shortened the malting process. At that occasion, the Dean of the Faculty of Science, Professor Philip G. Harper, mentioned that Macleod's association with the brewing industry puts her in the same fraternity as other scientists, such as James Watt (power), Louis Pasteur (pasteurisation), Peter Griess (colour chemistry), Joseph Williams Lovibond (colour physics), Gosset (statistics) and the man after whom the medal was named. He said that she was recognised nationally and internationally with distinction as a university teacher, scholar, scientist, technologist and as a brewer.
One of her PhD students, Geoff Palmer, first worked with her on the research of barley and they published numerous papers together. He then became her successor at the Heriot-Watt University.
Death and legacy.
Anna Macleod died at St Raphaels, Edinburgh on 13 August 2004.
Heriot-Watt University's Edinburgh campus has a residence hall named in her honour.
Heriot-Watt University's Brewing and Distilling department, as it is now called, started the Anna Macleod Scholarship with a financial gift she had bequeathed to that University in her will.


Albert Kurland

Albert Kurland (June 29, 1914 – December 7, 2008) was a psychiatrist and neuropsychopharmacologist at the Spring Grove State Hospital and the Maryland State Psychiatric Research Center. He was also affiliated with Johns Hopkins University as a research professor. He was a prolific researcher, conducting many studies on anti-psychotics, early research on the treatment of alcoholics using psychedelics and making integral contributions to the research unit at the Spring Grove State Hospital.
Early life.
Kurland was born June 29, 1914, in Edwardsville, Luzerne County, Pennsylvania to parents who had emigrated from the border region of Poland and Belarus. He moved to Baltimore and lived with other relatives as a teenager, completing his diploma at City College Baltimore in 1932.
Kurland completed his medical degree at the University of Maryland Medical School in 1940 and afterwards served as an assistant battalion surgeon under General Patton in World War II. Under Patton, Kurland encountered gruesome physical and psychological suffering among soldiers. He received a Legion of Merit medal for his valor.
Kurland explained that his combat experiences motivated him to engage in neuropsychiatric medicine:Well, I saw in combat an awful lot of stress. I saw a lot of stress reactions. I saw troops killed by friendly fire, and then the troopers shoot themselves. I saw all kinds of dreadful things….[So] I'd like to go to a neuropsychiatric unit if possible to learn something about this situation, and maybe, I might be able to find ways and means of being helpful in this areas.
Post-war developments.
Kurland received neuropsychiatric training at Mason General Hospital and then received a Fellowship in Neuropsychiatric Research at Sinai Hospital in East Baltimore while also working part-time at the Veterans' Administration.
Following these positions, Kurland arrived at Spring Grove State Hospital in 1946. At this time the hospital had roughly 2,700 patients and 23 psychiatrists. The physician-patient ratio was not conducive one on one doctor:patient consultations, and this motivated Kurland to explore new methods of treatment. In his spare time and without funding from Spring Grove, he began to explore the use of Thorazine (chlorpromazine) in psychiatric experiments.
By the mid-1950s, Kurland's efforts were recognized by Charles Savage and Lou Cholden at the National Institute for Mental Health (NIMH).
With his research opportunities increasing, Kurland founded Friends of Psychiatric Research to coordinate additional funding for, and to simplify the administration of, his research. Soon afterwards he was promoted to Director of Research at Spring Grove in 1953. He also received increasing support from Gene Brody at the University of Maryland and Joel Elkes at Johns Hopkins University at about this time. With additional funding from the state of Maryland, Kurland and his colleagues launched the Maryland Psychiatric Research Center.
As he conducted his research, Kurland founded the Maryland Psychiatric Research Center, of which he was the first director. The Center was built with $1.5 million of funding from state of Maryland in 1967.
Ten years after his appointment to the Maryland Psychiatric Research Center, Kurland was appointed to Research Associate in Psychiatry at the University of Maryland Medical School, in January 1977. The Center continues to operate today with eight active research programs, including neuroscience, neuroimaging research, and the Maryland Brain Collection program. Kurland also served as a Research Professor at Johns Hopkins University.
Near the end of his career, Kurland suggested that developments in psychotropic drugs alone were not sufficient to help individuals grow to their full capacity:There's much to be done but I think it will be done in the future, because we know the limitations of the drugs we're using today. We treat a panic disorder, we treat alcoholism, we treat depression, and we ameliorate the symptoms, but what are we doing so far that is adding to the individual's capacity for development?
Kurland's concern for the “individual's capacity for development” can be placed alongside the description that Kurland, “never said an unkind word about anyone.”
Contributions to neuropsychopharmocology.
Kurland published over 150 studies in the fields of psychiatry, in particular, neuropsychopharmacology. The figure shown at right presents the frequency of Kurland's published research by different treatment modalities.
Research on LSD as a Treatment.
With Cholden and Savage, Kurland published his first peer reviewed research on psychedelics in 1955. Entitled "Clinical reactions and tolerance to LSD in chronic schizophrenia," the study sought to ascertain reactions to LSD among “chronic, regressed, schizophrenic patients” so that results could be compared to earlier research that described reactions of LSD among other subjects. This information was preliminary to the study's second aim, which was to examine the clinical and therapeutic potential of LSD. The research team also sought to replicate research conducted by Abram Hoffer and Humphrey Osmond who had done earlier LSD research in Canada beginning in 1952.
Kurland's work with Cholden and Savage predated their efforts in the subsequent Spring Grove experiment.
Unlike previous research on LSD, Kurland and his peers administered LSD intramuscularly, providing better control of dosing patients who often did not swallow oral doses completely. The team also took steps to allow patients to adjust to new research settings such that any reactions to LSD would be independent of reactions associated with environmental change.
Kurland and his colleagues found that reactions to LSD in the regressed schizophrenic subjects had at least three types: (1) covert reactions, in which no striking behavioral change was observed (e.g. patients became withdrawn), (2) intensified reactions, in which subjects presented increased agitation, anxiety or delusion and (3) reversed reactions, in which behaviors changed dramatically from what was typical (e.g. hostile patients became friendly).  This research also found that tolerance to LSD was not entirely psychological in nature because cross-tolerance with brom-lysergic acid was present while cross-tolerance with mescaline was negative. Finally, the team provided observations of how much time was required before larger doses of LSD were necessary to have the same impact as an initial dose.
Kurland's research at Spring Grove was not unique. According to Dyck's analysis, there were at least 100 articles on LSD by 1951, over 500 by the end of the 1950s, and ten years later there were more than 1000. However, Kurland and his team developed a research program that was the most ambitious and longstanding of its kind. According to one of Kurland's subsequent co-authors:The body of research that emerged from these 23 years of study [at Spring Grove] remains the largest, most sustained and systematic research into therapeutic use of psychedelic drugs and psychotherapy yet attempted.
Kurland's 1955 research on LSD paused until the 1960s when Sanford Unger arrived at Spring Grove. Unger was a psychologist from Hollywood Hospital in Vancouver, British Columbia. By 1963, Kurland was collaborating with Unger and Charles Savage in renewed research, examining the efficacy of LSD in treating alcoholics and subsequently cancer patients.
Kurland's continued research on LSD in the 1960s and 1970s was complicated by the “moral panic” the general population had about the drug as well as by increased regulations for medical research. Additionally, LSD research posed methodological complications in observing the drug's effects on treatment and control groups. While the standard in medical research was a double-blind study, the effects of LSD were obvious to investigators. For these reasons, LSD research waned by the late 1970s. Today, however, research on the efficacy of psychedelics continues.
Research on antipsychotic compounds.
Kurland published with various colleagues nearly 50 studies on antipsychotics, beginning with his study of chlorpromazine (Thorazine) in 1955. Chlorpromazine had been shown to have useful applications by French psychiatrists Jean Delay and Pierre Deniker, and then in Canada under research directed by Heinz Lehmann. Kurland's first chlorpromazine study (1955) was conducted concurrently with research underway by Joel Elkes, who was examining the substance in 1954 from Birmingham, England. Kurland's research on the effectiveness of antipsychotics addressed numerous diseases, including schizophrenia, addiction, psychosis and other acute psychiatric illnesses.
Research on antidepressants.
Kurland published 14 articles on antidepressant medications, including nialamide, aletamine, dilantin, amoxapine among others. His later research included studies that aided the development of buproprion.
Other research.
Among his published research, Kurland analyzed a variety of other clinical treatments for depression, addiction, anxiety and other diseases. His investigations of haloanisone, pyridoxine, and perphenazine-benztropine mesylate, are examples of the broad range of compounds that Kurland studied while his focus on other antipsychotics and psychedelics continued. Even more publications evidence Kurland's examination of general topics in psychiatry not directly related to clinical treatments, but describe appropriate admission procedures for psychiatric patients or the role of patients' general practitioners.
Kurland's attempts to observe the human condition were not limited to traditional research methodology common in medical science. While he typically utilized standard methodological protocols in his published work, he also considered phenomena that did not easily fit within the quantitative, positivist perspectives common in medical research. For example, as described by his former colleague Stanislav Grof, Kurland invited Joan Grant and Dennys Kelsey, European therapists who used hypnotic therapy to assist patients uncover past lives, to a symposium to inform research on the compound.


Cyclobacterium xiamenense

Cyclobacterium xiamenense is a horseshoe-shaped, Gram-negative and non-motile bacterium from the genus of Cyclobacterium which has been isolated from the alga Chlorella autotrophica from the coastal sea of Xiamen in China.


Flavivirus capsid hairpin cHP

The Flavivirus capsid hairpin cHP is a conserved RNA hairpin structure identified within the capsid coding region of several flavivirus genomes. These positive strand RNA genomes are translated as a single polypeptide and subsequently cleaved into constituent proteins, the first of which is the capsid protein. The cHP hairpin is located within the capsid coding region between two AUG start codons. The cHP cis element has been shown to direct translation start from the suboptimal first start codon. The ability of cHP to direct initiation from the first start codon is proportional to its thermodynamic stability, is position dependent, and is sequence independent. It has been demonstrated that both AUGs and the conserved cHP are necessary for efficient viral replication in human and mosquito cells.


Cypress Systems

Cypress Systems, Inc. is a biotech company headquartered in Madera, California and is best known for its research, in collaboration with the National Cancer Institute (NCI), regarding the use of selenium supplementation for the prevention of a variety of cancers. Cypress Systems, Inc. also manufactures selenium, zinc, and chromium for the nutraceutical industry.
In 1983, the now-deceased Dr. Larry C. Clark conducted a Nutritional Prevention of Cancer (NPC) study. This historic trial claimed that selenium supplementation prevented a variety of cancers, a claim which has not been validated by later enquiry, as there is no good evidence selenium supplementation helps prevent cancer.
The Chief Science Officer (CSO) of Cypress is Mark Whitacre. In the 1990s, Whitacre spent 9 years in federal prison for embezzling over 9 million dollars from his former employer, ADM Archer Daniels Midland. He embezzled the funds while he was working with the FBI as a whistleblower. He is the highest level executive of a Fortune 500 company in US history to turn whistleblower.


Hebeloma aminophilum

Hebeloma aminophilum, commonly known as the ghoul fungus, is a species of mushroom in the family Hymenogastraceae. Found in Western Australia, it gets its common name from the propensity of the fruiting bodies to spring out of decomposing animal remains. Its edibility is unknown.
Taxonomy.
The ghoul fungus was first described by mycologists R.N. Hilton and Orson K. Miller, Jr. in 1987. The generic name is derived from the Ancient Greek "Hebe", "youth", and -"loma", a fringe (pertaining to the fungal veil), referring to how the fungal veil is only seen in immature specimens. It gets its common name of ghoul fungus from its habit of growing around animal carcasses. The holotype collection consisted of about 100 specimens that were fruiting around the bones of a decomposing kangaroo carcass that had been dumped some months before.
Description.
The dull pinkish brown or cream cap is in diameter, convex initially before flattening out with age. There is a slight umbo, and the cap margin is inrolled when young. A thin white veil rapidly disappears in young mushrooms. The cap surface is sticky initially. The adnate (or sometimes adnexed) gills are pale pink to pinkish brown and up to 1 cm deep. With age, they can be encrusted with clumps of spores. The cylindrical stipe is high, in diameter and has a thickened base and lacks a ring. The thick flesh is cream or pale yellow, with a bitter taste and a stale smell. The spore print is pinkish brown, and the oval spores measure 8.5 by 4.9 μm. The mycelium is white.
Similar species include the introduced poisonpie ("Hebeloma crustuliniforme"), which has been recorded in pine plantations, the native western Australian poisonpie ("H. westraliense"), which does not grow near carcasses, and the Australian white webcap ("Cortinarius austroalbidus"), which is paler and smells of curry.
Distribution and habitat.
An uncommon fungus, "Hebeloma aminophilum" is found in southern Western Australia, southeastern South Australia and Victoria. Fruiting bodies arise in eucalyptus woodland in the vicinity of sheep, reptile and bird carcasses. The habit of growing from flesh gives it the term sarcophilous.


Mini-ykkC RNA motif

The mini-ykkC RNA motif (later renamed Guanidine-II riboswitch) was discovered as a putative RNA structure that is conserved in bacteria. The motif consists of two conserved stem-loops whose terminal loops contain the RNA sequence ACGR, where R represents either A or G. Mini-ykkC RNAs are widespread in Proteobacteria, but some are predicted in other phyla of bacteria. It was expected that the RNAs are cis-regulatory elements, because they are typically located upstream of protein-coding genes.
The genes that are apparently controlled by mini-ykkC RNAs bear a resemblance to the genes controlled by ykkC-yxkD leader (guanidine-I), and nine gene families are common to both. Therefore, it was proposed that these two RNA classes have the same function. The complex structure and many conserved nucleotides found in the ykkC-yxkD leader are not present in the mini-ykkC RNA motif. Despite this, it was shown that each of the mini-ykkC two stem-loop structures directly binds free guanidine. Therefore, mini-ykkC RNA motif represents a distinct class of guanidine-sensing RNAs called Guanidine-II riboswitch. Its crystal structure was also determined.


Invertible knot

In mathematics, especially in the area of topology known as knot theory, an invertible knot is a knot that can be continuously deformed to itself, but with its orientation reversed. A non-invertible knot is any knot which does not have this property. The invertibility of a knot is a knot invariant. An invertible link is the link equivalent of an invertible knot.
There are only five knot symmetry types, indicated by chirality and invertibility: fully chiral, reversible, positively amphichiral noninvertible, negatively amphichiral noninvertible, and fully amphichiral invertible.
Background.
It has long been known that most of the simple knots, such as the trefoil knot and the figure-eight knot are invertible. In 1962 Ralph Fox conjectured that some knots were non-invertible, but it was not proved that non-invertible knots exist until Hale Trotter discovered an infinite family of pretzel knots that were non-invertible in 1963. It is now known almost all knots are non-invertible.
Invertible knots.
All knots with crossing number of 7 or less are known to be invertible. No general method is known that can distinguish if a given knot is invertible. The problem can be translated into algebraic terms, but unfortunately there is no known algorithm to solve this algebraic problem.
If a knot is invertible and amphichiral, it is fully amphichiral. The simplest knot with this property is the figure eight knot. A chiral knot that is invertible is classified as a reversible knot.
Strongly invertible knots.
A more abstract way to define an invertible knot is to say there is an orientation-preserving homeomorphism of the 3-sphere which takes the knot to itself but reverses the orientation along the knot. By imposing the stronger condition that the homeomorphism also be an involution, i.e. have period 2 in the homeomorphism group of the 3-sphere, we arrive at the definition of a strongly invertible knot. All knots with tunnel number one, such as the trefoil knot and figure-eight knot, are strongly invertible.
Non-invertible knots.
The simplest example of a non-invertible knot is the knot 817 (Alexander-Briggs notation) or .2.2 (Conway notation). The pretzel knot 7, 5, 3 is non-invertible, as are all pretzel knots of the form (2"p" + 1), (2"q" + 1), (2"r" + 1), where "p", "q", and "r" are distinct integers, which is the infinite family proven to be non-invertible by Trotter.


Ernst Leopold Salkowski

Ernst Leopold Salkowski (October 11, 1844 – March 8, 1923) was a German biochemist who was a native of Königsberg.
He received his education at the University of Königsberg, later working in Berlin as an assistant in the chemical laboratory of Rudolf Virchow's institute of pathology (1872). In 1874 he became an associate professor of medicinal chemistry in Berlin, followed by an assignment as departmental head (1880). In 1909 he was honored with the title of "full professor".
Salkowski specialized in the fields of physiological and pathological chemistry, also making contributions in the related fields of pharmacology, analytical chemistry and hygiene. In 1890 he was the first to describe tissue autolysis, of which he referred to as "auto-digestion". He is remembered for developing tests for detection of various compounds and substances, such as cholesterol, creatinine, glucose, carbon monoxide, and indole. In 1892 (with Jastrowitz) he was the first to describe pentosuria.
He was the author of "Practicum der physiologischen und pathologischen Chemie", later translated into English as "A Laboratory Manual of Physiological and Pathological Chemistry". With internist Wilhelm von Leube (1842-1922), he published "Die Lehre vom Harn" (The doctrine of urine).


Harry Gold

Harry Gold (born Henrich Golodnitsky, December 11, 1910 – August 28, 1972) was a Swiss-born American laboratory chemist who is known for having been convicted as a courier for the Soviet Union to pass atomic secrets from Klaus Fuchs, an agent of the Soviet Union, during World War II. Gold served as a government witness and testified in the case of Julius and Ethel Rosenberg, who were convicted and executed in 1953 for their roles. Gold served 15 years in prison.
Born in Bern, Switzerland, to parents from the Russian Empire, Gold had immigrated to the US with his parents as a child at the age of four. They settled in Philadelphia. During the Great Depression, he found work and finished his degree in chemistry at night. He returned to work as a clinical chemist after release from prison.
Early life.
Heinrich Golodnitsky was born on December 12, 1910, in Bern, Switzerland to Samson and Celia (Ominsky) Golodnitsky, both Jewish immigrants from what is now Ukraine and was then part of the Russian Empire. Samson had grown up in Smila, where his father was a successful merchant. He was sent to Switzerland for additional schooling, as opportunities for Jews were limited in Russia, but he was already influenced by reading Leo Tolstoy, and chose to go into woodworking. He became a carpenter. Henrich's mother Celia had first emigrated from central Ukraine (Russia) as a teenager to Paris, where she studied dentistry. She had become radicalized in Russia and supported the Zionist movement. After running out of money, she took a job in a cigar factory in Bern, where she met Samson. They married about 1907 or 1908.
When Heinrich was 4, his family immigrated to the United States, seeking more opportunity. After they arrived at New York in July 1914, an agent at Ellis Island suggested they shorten their surname to Gold, which they agreed to, and they kept that version. In the United States, the boy became known as Harry. They first went to Chicago, where Sam worked in a coalyard and Celia in a tobacco factory, both limited by their lack of English. After a year, they left. Sam went to Norfolk, Virginia, where he had some relatives. Celia took their son to Philadelphia, where her brother Shama had settled. When the shipyard job and conditions in Norfolk did not work out, Sam joined them in Philadelphia, a major industrial city. They settled in South Philadelphia in 1915 in the Jewish section. Ethnic Irish occupied territory to the north, and Italians to the west. After some other jobs, Sam found work as a cabinetmaker at the Victor Talking Machine Company in Camden, New Jersey, across the Delaware River.
In 1917, Gold’s mother had another son, named Yussel (Joseph) after a grandfather. Neighbors on Philip Street later described the Gold family as having been unusually quiet and stand-offish, but Harry Gold said he had a happy and secure childhood. He greatly enjoyed learning and was a good student in school. To supplement Sam's modest earnings, Celia taught Hebrew and Yiddish to neighborhood children, and was considered an excellent teacher. She expanded the lessons with Jewish folklore and Hebrew literature.
But in the early 20th century, immigrant groups in Philadelphia clashed over their territories; Gold as a boy in the neighborhood suffered with this, especially since he was small and slight, and non-athletic. His father complained of discrimination by newly hired Italian immigrants at the Victor Company, where he was one of the few Jews. In the mid-1920s an Irish foreman tried to drive him out of the factory, but he persisted. Gold admired his father's stoicism but resented the conflicts and developed a desire to fight prejudice. He had an early interest in chemistry and graduated from South Philadelphia High School in 1929.
Early career.
After high school graduation, Gold was offered a job by one of his father’s acquaintances at Giftcrafters, a woodworking firm in the northern Kensington section of the city.
While looking for other positions, Gold applied and gained a job at the Pennsylvania Sugar Company, located on the banks of the Delaware River. A job there would give him economic security and the chance to work with college-educated chemists and state-of-the art labs. He saved money from his work and attended the University of Pennsylvania full time from 1930 to 1932 before his money ran out. The Great Depression was unfolding and he returned to PA Sugar to help his family.
Great Depression, work, and espionage.
Gold had expressed interest in the Socialist Party early in life, influenced by his mother, and the family bought the "Jewish Daily Forward". He later said that he thought Communism was related to "a wild and vaguely defined phenomenon going on in a primitive country thousands of miles away." For other Americans, the economic crisis challenged faith in capitalism. A week before Christmas 1932, Gold was laid off by the sugar company. Both Harry and his father Sam looked for work each morning, to no avail. The Gold family faced economic ruin.
Gold was offered a job by Tom Black, a former classmate, at the Holbrook Manufacturing Company in Jersey City. Black befriended him and tried to recruit Gold to the Communist Party. Grateful to Black for his friendship and a chance to work, Gold reluctantly became involved. But he continued to hold his views against the Party. When Gold found that the PA Sugar Company was hiring at the same salary he was making, he decided to return to the company, Philadelphia, and his family. Black visited Gold and his family, all the while encouraging him to attend communist meetings and join the party.
In 1934, Gold started passing industrial secrets to Black from the sugar company. During this time, Gold also attended Drexel Institute of Technology, and took night courses in chemistry, to keep working toward his goal in chemistry.
In 1940, Jacob Golos activated Gold for Soviet espionage, but he was not a recruited agent of the "rezidentura." In the late 1940s, Soviet Case Officer Semyon Semenov appropriated Gold from Golos for use by the NKVD. Gold became a formally recruited Soviet agent at this time, and was assigned the codename "GUS, GOS," or "GOOSE." Semenov remained Gold's control officer until March 1944.
After the war, tensions increased between the US and the Soviet Union following its takeover of territory in Eastern Europe. Communist governments led East Germany, Poland, Yugoslavia, and other eastern nations dominated by the Soviet Union. The Cold War between the US and the Soviet Union had begun.
In 1950, Klaus Fuchs, an NKVD agent, was arrested in England and charged with espionage. Fuchs confessed that while working in the United States during World War II, he had passed information about the atom bomb to the Soviet Union, then a US ally. Fuchs denied working with other spies, except for a courier who collected information from him. When initially shown photographs of suspects, including Gold, he failed to identify him. After prompting by the prosecution, he identified Gold.
Gold was arrested that year. Under interrogation by US officials, he admitted that he had been involved in espionage since 1934 and had helped Fuchs pass information about the Manhattan Project to the Soviet Union by way of Soviet General Consul Anatoli Yakovlev. Gold's confession identified many other people connected to the espionage network, and led to the arrest of David Greenglass. He had worked as a machinist at the Manhattan Project and passed material to Gold. Greenglass's testimony resulted in the arrest in 1950 of his sister Ethel and her husband Julius Rosenberg, who were also charged with conspiracy to commit espionage. Gold cooperated and was a government witness in the trial of the Rosenbergs, as was Greenglass. The latter's testimony contributed to their convictions and death sentences; they were executed.
Unable to make the $100,000 bail, Gold was jailed for 7 and a half months before his trial. In 1951, he was convicted and sentenced to 30 years' imprisonment. In May 1965, one of his appeals resulted in his being paroled for good behavior after serving less than half that time. He was also credited for the time in jail before his trial.
Gold returned to Philadelphia. He worked as a clinical chemist in the pathology lab of John F. Kennedy Memorial Hospital, and ultimately for the chief pathologist. He died on August 28, 1972, during heart surgery, at the age of 61. He had never married. He was interred in Har Nebo Cemetery in Philadelphia County, Pennsylvania.


Metabotropic glutamate receptor 2

Metabotropic glutamate receptor 2 (mGluR2) is a protein that, in humans, is encoded by the "GRM2" gene. mGluR2 is a G protein-coupled receptor (GPCR) that couples with the Gi alpha subunit. The receptor functions as an autoreceptor for glutamate, that upon activation, inhibits the emptying of vesicular contents at the presynaptic terminal of glutamatergic neurons.
Structure.
In humans, mGluR2 is encoded by the "GRM2" gene on chromosome 3. At least three protein-coding isoforms are predicted based on genomic information, as well as numerous non-coding isoforms. The mGluR2 protein is a seven-pass transmembrane protein.
Function.
In humans, mGluR2 is only expressed in the brain, and not in any other tissue. In the brain, mGluR2 is expressed in neurons as well as astrocytes. Subcellularly, mGluR2 is predominantly positioned at the presynaptic terminal, although it is also expressed at the postsynaptic terminal.
The metabotropic glutamate receptors are a family of G protein-coupled receptors, that have been divided into 3 groups on the basis of sequence homology, putative signal transduction mechanisms, and pharmacologic properties: Group I includes GRM1 and GRM5 and these receptors have been shown to activate phospholipase C. Group II includes mGluR2 (this receptor) and GRM3 while Group III includes GRM4, GRM6, GRM7 and GRM8. Group II and III receptors are linked to the inhibition of the cyclic AMP cascade but differ in their agonist selectivities.
Protein–protein interactions.
mGluR2 is able to form a heteromeric complex with various other different GPCRs. One example is with isoform mGluR4. The mGluR2-mGluR4 heteromer exhibits a pharmacological profile distinct from the parent receptor monomers. Another example is with serotonin receptor 2A (5HT2A); see below.
Pharmacology.
The development of subtype-2-selective positive allosteric modulators (PAMs) experienced steady advance in recent years. mGluR2 potentiation is a new approach for the treatment of schizophrenia. On the other hand, antagonists and negative allosteric modulators of mGluR2/3 have potential as antidepressant drugs.
Role in hallucinogenesis.
Many psychedelic drugs (e.g. LSD-25) produce their effects by binding to the oligomerized complexes of the 5HT2A and mGlu2 receptors. Lisuride acts preferentially or exclusively on the non-heteromerized 5HT2A receptors, which are not capable of inducing psychedelic effects. Due to this, lisuride is capable of reducing the hallucinogenic effects of these drugs through competitive antagonistic activity (producing the effect of a silent antagonist in the presence of these drugs).
Strong agonists for either subunit of the 5HT2A-mGlu2R heterocomplex suppress signaling through the partner subunit and inverse agonists for either subunit potentiate the signaling through the partner subunit.
Role in rabies virus infection.
mGluR2 has been found to be a novel receptor for rabies virus. The virus has a glycoprotein on its surface which interacts with the receptor. Rabies virus can bind to mGLuR2 directly and the virus-receptor complex is internalized into the cell together. The complex is then transported into early and late endosomes. Rabies virus enters the cells by clathrin-independent endocytosis which could suggest that mGLuR2 also uses this pathway. It is still to be clarified whether the Rabies virus glycoprotein can act as a PAM or NAM and in such a way affect the function of the receptor.


Sarcosine reductase

In enzymology, a sarcosine reductase () is an enzyme that catalyzes the chemical reaction
The 3 substrates of this enzyme are acetyl phosphate, methylamine, and thioredoxin disulfide, whereas its 3 products are N-methylglycine, phosphate, and thioredoxin.
This enzyme belongs to the family of oxydoreductases, specifically those acting on X-H and Y-H to form an X-Y bond with a disulfide as acceptor. The systematic name of this enzyme class is acetyl-phosphate methilamine:thioredoxin disulfide oxydoreductase (M-methylglycine-forming).


Dinoxyline

Dinoxyline is a synthetic compound developed for scientific research, which acts as a potent full agonist at all five dopamine receptor subtypes.


Interleukin 8 receptor, alpha

Interleukin 8 receptor, alpha is a chemokine receptor. This name and the corresponding gene symbol IL8RA have been replaced by the HGNC approved name C-X-C motif chemokine receptor 1 and the approved symbol CXCR1. It has also been designated as CD181 (cluster of differentiation 181). The IUPHAR Committee on Receptor Nomenclature and Drug Classification use the HGNC recommended name, CXCR1.
Function.
The protein encoded by this gene is a member of the G-protein-coupled receptor family. This protein is a receptor for interleukin 8 (IL8). It binds to IL8 with high affinity, and transduces the signal through a G-protein-activated second messenger system. Knockout studies in mice suggested that this protein inhibits embryonic oligodendrocyte precursor migration in developing spinal cord. This gene, IL8RB, a gene encoding another high affinity IL8 receptor, and IL8RBP, a pseudogene of IL8RB, form a gene cluster in a region mapped to chromosome 2q33-q36. Stimulation of CXCR1 in neutrophils by its primary ligand, Interleukin 8, leads to neutrophil chemotaxis and activation.
Clinical significance.
Blocking CXCR1 (e.g., with repertaxin) inhibits some human breast cancer stem cells (in vitro and in mice).
In malignant melanoma expression of CXCR1 at the cell surface is present, independent of the cancers stage. It is thought to have a role in the cell growth and angiogenesis required for tumour survival. In this way it has been identified as a potential therapeutic target.
CXCR1 can be cleaved and inactivated by Neutrophil Derived Serine Proteases (NSPs), leading to neutrophil dysfunction and impaired bacterial killing in cystic fibrosis lung disease.
Interactions.
Interleukin 8 receptor, alpha has been shown to interact with GNAI2.


Pseudoglutamicibacter cumminsii

Pseudoglutamicibacter cumminsii is a species of Gram-positive bacteria.


Hsp90 cis-regulatory element

The Hsp90 cis regulatory element is an RNA element (RNA thermometer) found in the 5' UTR of the "Drosophila" hsp90 mRNA. It is required for increased translational efficiency during the heat shock response.
The hsp90 gene product is involved in the "Drosophila" heat shock response. Translation of the hsp90 mRNA is very inefficient under normal growth temperatures, when heat shock occurs translation becomes more efficient. This is mediated though this regulatory element.


N-methylalanine dehydrogenase

In enzymology, a N-methylalanine dehydrogenase () is an enzyme that catalyzes the chemical reaction
The 3 substrates of this enzyme are N-methyl-L-alanine, H2O, and NADP+, whereas its 4 products are pyruvate, methylamine, NADPH, and H+.
This enzyme belongs to the family of oxidoreductases, specifically those acting on the CH-NH2 group of donors with NAD+ or NADP+ as acceptor. The systematic name of this enzyme class is N-methyl-L-alanine:NADP+ oxidoreductase (demethylating, deaminating).