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 ...