Monoaminergic systems Before the discovery of<unk> , trace amines were believed to serve very limited functions. They were thought to induce noradrenaline release from sympathetic nerve endings and compete for catecholamine or serotonin binding sites on cognate receptors, transporters, and storage sites. Today, they are believed to play a much more dynamic role by regulating monoaminergic systems in the brain. One of the downstream effects of active<unk>  is to increase cAMP in the presynaptic cell via Gαs G-protein activation of adenylyl cyclase. This alone can have a multitude of cellular consequences. A main function of the cAMP may be to up-regulate the expression of trace amines in the cell cytoplasm. These amines would then activate intracellular<unk> . Monoamine autoreceptors (e.g., D2 short, presynaptic α2, and presynaptic 5-HT1A) have the opposite effect of<unk> , and together these receptors provide a regulatory system for monoamines. Notably, amphetamine and trace amines possess high binding affinities for<unk> , but not for monoamine autoreceptors. The effect of<unk>  agonists on monoamine transporters in the brain appears to be site-specific. Imaging studies indicate that monoamine reuptake inhibition by amphetamine and trace amines is dependent upon the presence of<unk>  in the associated monoamine neurons. As of 2010, of<unk>  and the dopamine transporter (DAT) has been visualized in rhesus monkeys, but of<unk>  with the norepinephrine transporter (NET) and the serotonin transporter (SERT) has only been evidenced by messenger RNA (mRNA) expression. In neurons with<unk> ,<unk>  agonists increase the concentrations of the associated monoamines in the synaptic cleft, thereby increasing post-synaptic receptor binding. Through direct activation of G protein-coupled inwardly-rectifying potassium channels (GIRKs),<unk>  can reduce the firing rate of dopamine neurons, in turn preventing a hyper-dopaminergic state. Amphetamine and trace amines can enter the presynaptic neuron either through or by diffusing across the neuronal membrane directly. As a consequence of DAT uptake, amphetamine and trace amines produce competitive reuptake inhibition at the transporter. Upon entering the presynaptic neuron, these compounds activate<unk>  which, through protein kinase A (PKA) and protein kinase C (PKC) signaling, causes DAT phosphorylation. Phosphorylation by either protein kinase can result in DAT internalization ( reuptake inhibition), but phosphorylation alone induces reverse transporter function (dopamine efflux). Immune system Expression of<unk>  on lymphocytes is associated with activation of lymphocyte immuno-characteristics. In the immune system,<unk>  transmits signals through active PKA and PKC phosphorylation cascades. In a 2012 study, Panas et al. observed that methamphetamine had these effects, suggesting that, in addition to brain monoamine regulation, amphetamine-related compounds may have an effect on the immune system. A recent paper showed that, along with<unk> ,<unk>  is required for full activity of trace amines in PMN cells. Phytohaemagglutinin upregulates mRNA in circulating leukocytes; in these cells,<unk>  activation mediates leukocyte chemotaxis toward<unk>  agonists.<unk>  agonists (specifically, trace amines) have also been shown to induce interleukin 4 secretion in T-cells and immunoglobulin E (IgE) secretion in B cells. Astrocyte-localized<unk>  regulates EAAT2 levels and function in these cells; this has been implicated in methamphetamine-induced pathologies of the neuroimmune system.
TAAR1
INAH 3
PIM2
SMN1
JAMA
MCN
PANO1
CSTX