CHAPTER 8: Atypical Neurotransmitters

KEY CONCEPTS

• 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.

INTRODUCTION

Atypical neurotransmitters include a host of intercellular signaling molecules that ...