Crystallographic structural studies of a potassium channel have shown that, when a potential difference is introduced over the membrane, the associated electric field induces a conformational change in the potassium channel. The conformational change distorts the shape of the channel proteins sufficiently such that the cavity, or channel, opens to allow influx or efflux to occur across the membrane. This movement of ions down their concentration gradients subsequently generates an electric current sufficient to depolarize the cell membrane.<unk><unk>  sodium channels and calcium channels are made up of a single polypeptide with four homologous domains. Each domain contains 6 membrane spanning alpha helices. One of these helices, S4, is the<unk>  sensing helix. The S4 segment contains many positive charges such that a high positive charge outside the cell repels the helix, keeping the channel in its closed state. In general, the<unk>  sensing portion of the ion channel is responsible for the detection of changes in transmembrane potential that trigger the opening or closing of the channel. The S1-4 alpha helices are generally thought to serve this role. In potassium and sodium channels,<unk> -sensing S4 helices contain positively-charged lysine or arginine residues in repeated motifs. In its resting state, half of each S4 helix is in contact with the cell cytosol. Upon depolarization, the positively-charged residues on the S4 domains move toward the exoplasmic surface of the membrane. It is thought that the first 4 arginines account for the gating current, moving toward the extracellular solvent upon channel activation in response to membrane depolarization. The movement of 10–12 of these protein-bound positive charges triggers a conformational change that opens the channel. The exact mechanism by which this movement occurs is not currently agreed upon, however the canonical, transporter, paddle, and twisted models are examples of current theories. Movement of the<unk> -sensor triggers a conformational change of the<unk> of the conducting pathway, controlling the flow of ions through the channel. The main functional part of the<unk> -sensitive protein domain of these channels generally contains a region composed of S3b and S4 helices, known as the "paddle" due to its shape, which appears to be a conserved sequence, interchangeable across a wide variety of cells and species. A similar<unk>  sensor paddle has also been found in a family of<unk>  sensitive phosphatases in various species. Genetic engineering of the paddle region from a species of volcano-dwelling archaebacteria into rat brain potassium channels results in a fully functional ion channel, as long as the whole intact paddle is replaced. This "modularity" allows use of simple and inexpensive model systems to study the function of this region, its role in disease, and pharmaceutical control of its behavior rather than being limited to poorly characterized, expensive, and/or difficult to study preparations. Although<unk> s are typically activated by membrane depolarization, some channels, such as inward-rectifier potassium ion channels, are activated instead by hyperpolarization. The<unk> is thought to be coupled to the<unk>  sensing regions of the channels and appears to contain a mechanical obstruction to ion flow. While the S6 domain has been agreed upon as the segment acting as this obstruction, its exact mechanism is unknown. Possible explanations include: the S6 segment makes a scissor-like movement allowing ions to flow through, the S6 segment breaks into two segments allowing of passing of ions through the channel, or the S6 channel serving as the<unk> itself. The mechanism by which the movement of the S4 segment affects that of S6 is still unknown, however it is theorized that there is a S4-S5 linker whose movement allows the opening of S6. Inactivation of ion channels occurs within milliseconds after opening. Inactivation is thought to be mediated by an intracellular<unk> that controls the opening of the pore on the inside of the cell. This<unk> is modeled as a ball tethered to a flexible chain. During inactivation, the chain folds in on itself and the ball blocks the flow of ions through the channel. Fast inactivation is directly linked to the activation caused by intramembrane movements of the S4 segments, though the mechanism linking movement of S4 and the engagement of the inactivation<unk> is unknown.
Voltage-gated ion channel
Cyclic nucleotide–gated ion channel
G protein-gated ion channel
Mechanosensitive channels
Neurotransmitter transporter
Glutamate transporter
Carboxylate transporter
Sodium-chloride symporter