Kaplan + Sadock's Synopsis of Psychiatry, 11e

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Chapter 1: Neural Sciences

Figure 1.4-12 Neurotransmitter and signaling functions of nitric oxide (NO) via production of cyclic guanosine monophosphate (cGMP). Gaseous nitric oxide is enzymatically generated and freely diffuses into an adjacent neuron ( upper right ). In comparison to traditional neurotransmitters ( upper left ), nitric oxide (NO) does not act via a specific neurotransmitter receptor on the surface membrane of a neuron. In contrast, NO freely diffuses across the neuronal membrane and activates the enzyme, guanylyl cyclase, which converts guanosine 5’-triphosphate (GTP) into the second messenger, cGMP. Nitric oxide effects are mediated, in part, by cGMP activation of neuronal protein kinases, new gene expression, and effects on neuronal long-term potentiation (LTP) and long-term depression (LTD). ATP, adenosine triphosphate. (From Sadock BJ, Sadock VA, Ruiz P. Kaplan & Sadock’s Comprehensive Textbook of Psychiatry . 9 th ed. Philadelphia: Lippincott Williams & Wilkins; 2009:104.)

process termed protein nitration, and deoxyribonucleic acid (DNA), leading to cellular dysfunction. Cell loss resulting from ischemic stroke is mediated in part by overstimulation of the glutamate NMDA receptor, a process termed excitotoxicity. Nitric oxide produced by NMDA activa- tion appears to mediate a significant portion of this excitotoxic neuronal death, and stroke damage is reduced in mice with a genetic deletion of nNOS. S-Nitrosylation has also been implicated in pathologic processes in the brain. Mutations in the Parkin protein are associated with early onset Parkinson’s disease. Parkin is an E3 ubiquitin ligase, adding ubiquitin molecules to proteins and targeting them for destruction in the cell pro- teasome. In sporadic Parkinson’s disease (i.e., without the early onset mutation), nitric oxide can nitrosylate the Parkin protein and inhibit its protective E3 ubiquitin ligase function. An overabundance of nitric oxide signaling may thus predispose to the dysfunction and cell death of dopaminergic neurons in Parkinson’s disease by interfering with proteins essential for cell functioning. In Alzheimer’s disease excess oxidation of brain protein, lipids, and carbohydrates has long been appreciated, but nitrosative stress from excess nitric oxide also appears to participate in the disease. Protein disulfide isomerase (PDI) is a cellular protective

protein that may help combat the accumulation of misfolded proteins such as the amyloid fibrils occurring in the disease. In both Alzheimer’s and Parkinson’s disease brains, PDI appears to be S-nitrosylated in a harmful way that impedes its cellular protective function. The discovery that nitric oxide participates in neurodegenerative processes raises the possibility for improved diagnostic processes, such as detecting damage to cellular components produced by nitric oxide prior to the onset of full-blown symptoms. In addition, drugs may be designed to attenuate the damage to crucial neuronal proteins that pro- tect against disease onset. However, completely and nonspecifically inhibiting or stimulating NOS is likely to produce significant side effects because of its wide-ranging activities throughout the body. Carbon Monoxide Although carbon monoxide (CO) is most well known as an air pollutant derived from combustion reactions, it is produced phys- iologically in a great variety of organisms ranging from human to bacterium. Once thought to be a toxic byproduct of metabolic reactions, carbon monoxide is increasingly recognized to play an important role in regulating a variety of physiological processes