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The common designation of a group of neurotransmitters as purines is a misnomer; what are called purinergic signaling molecules are the nucleoside and nucleotide derivatives of purine and perhaps pyrimidine bases.
The two principal purinergic signaling molecules are adenosine and adenosine triphosphate (ATP). ATP is stored in small synaptic vesicles and released in a Ca2+-dependent fashion, whereas adenosine is released from nonvesicular cytoplasmic stores, likely via bidirectional nucleoside transporters.
Purine receptors form a relatively large and diverse group and have been categorized as P1 and P2 receptors.
P1 receptors, also called adenosine receptors, bind adenosine and its analogs and are G protein–coupled. Stimulant drugs of the methylxanthine family, including caffeine, are antagonists of adenosine receptors. P2 receptors consist of both ligand-gated ion channels termed P2X receptors and G protein–coupled receptors termed P2Y receptors. P2X receptors play an important role in pain processing.
Cannabinoids, the principal active ingredients of marijuana, primarily act in the brain on the CB1 receptor, a G protein–coupled receptor found on presynaptic terminals in the central nervous system (CNS).
Anandamide and 2-arachidonylglycerol are endogenous cannabinoids (endocannabinoids), which are released from postsynaptic cells and activate presynaptic CB1 receptors.
Nitric oxide (NO) is generated from arginine by NO synthase, which is stimulated by activation of postsynaptic NMDA receptors and increases in cellular Ca2+ levels. It diffuses out of cells and activates soluble guanylyl cyclase leading to the production of cGMP in adjacent cells and nerve terminals.
Carbon monoxide (CO) is produced by the breakdown of heme by heme oxygenase-2 and also may function as an atypical, diffusible messenger. Hydrogen sulfide (H2S) is another “gas transmitter”: it is generated from cyst(e)ine by the enzyme cystathionine β-synthase.
Neurotrophic factors are polypeptides or small proteins that support the growth, differentiation, and survival of neurons. They produce their effects by activation of tyrosine kinases.
The neurotrophins, which comprise nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF), and neurotrophin-3 (NT-3) and neurotrophin-4 (NT-4), act by binding to a family of tropomyosin receptor kinase (Trk) receptors, TrkA, TrkB, and TrkC, with intrinsic tyrosine kinase activity.
Numerous other growth factors, such as glial cell line–derived neurotrophic factor (GDNF), vascular endothelial growth factor (VEGF), and neuregulin, are important in regulating the nervous system.
Several cytokine-like factors, including ciliary neurotrophic factor (CNTF) and interleukin-6 (IL-6), are characterized by binding to receptors that activate a family of protein tyrosine kinases called Janus kinases (JAKs), which in turn activate transcription factors called signal transducers and activators of transcription (STATs).
Many additional cytokines, best understood for their role in the immune system and inflammatory responses, also are important in the regulation of CNS function. Prominent examples include interleukin-1 (IL-1), tumor necrosis factor-α (TNF-α), and transforming growth factor-β (TGF-β).
Chemokines are small proteins involved in immune responses; in the brain, chemokines are expressed predominately by microglia.
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Atypical neurotransmitters include a host of intercellular signaling molecules that have unusual ...