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  • Atypical neurotransmitters comprise a diverse group of intercellular signaling molecules with nonclassic neurotransmitter properties.

  • The two principal purinergic signaling molecules are adenosine and adenosine triphosphate (ATP). ATP is stored in small synaptic vesicles (with classic neurotransmitters) and released in a Ca2+–dependent fashion, whereas adenosine is either generated extracellularly from ATP or released from nonvesicular cytoplasmic stores, likely via bidirectional nucleoside transporters.

  • Purine receptors form a large and diverse group and are 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. Both 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 mostly on presynaptic terminals in the central nervous system (CNS).

  • Anandamide and 2-arachidonylglycerol, derived from phospholipids, are endogenous cannabinoids (endocannabinoids). They are released from postsynaptic cells, activate CB1 receptors on nearby presynaptic nerve terminals, and thereby inhibit neurotransmitter release from those terminals.

  • 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 putative “gas transmitter”: it is endogenously generated from cysteine by the enzyme cystathionine β-synthase and is implicated in neuromodulatory roles.

  • 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), 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 produced mainly by microglia and astrocytes and are crucial ...

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