Many of the unconventional transmitters do not fit the well-accepted neurotransmitter criteria mentioned at the beginning of this chapter. A handful of unconventional transmitters have been characterized and may ultimately prove to have relevance for neuropsychiatric disorders; here, we limit ourselves to a discussion of the gases nitric oxide (NO) and carbon monoxide (CO), which have been demonstrated to exhibit neurotransmitter-like properties in the brain (Dawson and Snyder 1994). The gases, as a result of being small and uncharged, are able to permeate the lipid bilayer and enter the neuron and directly affect certain second-messenger generating systems directly.
Synthesis of NO is derived from arginine via an enzymatic reaction involving NO synthase, flavin adenine dinucleotide, and flavin mononucleotide enzyme (Cooper et al. 2001). Currently, there are three different variations of NO synthase, which arise from different genes that share approximately 50% sequence homology. The neuronal NO synthase is activated by Ca2+ and calmodulin and is also regulated by phosphorylation, which decreases its function. NO is released from both neurons and glia and can activate the enzyme guanylate cyclase to augment cGMP concentrations, thereby regulating a variety of neurotransmitter systems (Cooper et al. 2001) (Figure 1-10). These effects likely occur via the activation of protein kinase G (termed G because it is activated by cGMP), but this remains to be definitely established. Notably, endocannabinoids, a class of fatty acid derivatives that bind to cannabinoid receptors, exert prominent effects on NO signaling (Alger 2005).
FIGURE 1-10. Nitric oxide as a signaling molecule.
This figure depicts the various regulatory processes involved in nitric oxide (NO) signaling. Reactive oxygen species, in particular several gases, represent yet another means by which the brain is able to transmit messages. NO is formed via NO synthase (NOS), an enzyme that is generally activated by Ca2+-calmodulin. As such, Ca2+ entry into cells via NMDA (N-methyl-D-aspartate) receptor activation is an important means of activating NOS. NOS yields NO by converting arginine to citrulline using O2. NO then converts GTP to cGMP, which then is able to target soluble guanylyl cyclases (GCs) (enzymes that are similar to adenylyl cyclases but are activated by cGMP rather than cAMP). cGMP then activates the protein kinase (PKG) and, through the conversion of ATP to ADP, phosphorylates many proteins to bring about the physiological effects of NO. Once produced, NO is then able to diffuse out of the neuron and act on other cells as a signaling molecule. Interestingly, NO is able to also diffuse back to the presynaptic terminal, acting as a retrograde transmitter, and is thought to be important in reshaping synaptic connections (i.e., it has been linked to long-term potentiation). NO is labeled in yellow; glutamate is labeled in purple. GTg = glial transporter for g I uta mate; GTn = neuronal transporter for gl uta mate; 5-HTia = serotoniniA receptor; S1003 = calcium-binding protein expressed primarily by astrocytes.
Source. Adapted from Girault J-A, Greengard P: "Principles of Signal Transduction," in Neurobiology of Mental Illness. Edited by Charney DS, Nestler EJ, Bunney BS. New York, Oxford University Press, 1999. Copyright 1999, Oxford University Press. Used with permission.
CO appears to be formed in neurons exclusively by heme oxygenase-2 (HO-2), which cleaves the heme ring, releasing biliverdin, expelling iron from the heme ring, and releasing a one-carbon fragment as CO. HO-2 activity occurs in neuronal populations in numerous parts of the brain and is dynamically regulated by neuronal impulses through a kinase cascade in which PKC activates casein kinase-2, which in turn phosphorylates and activates HO-2. HO-2 activity generates low micromolar concentrations of CO in the brain.
Similar to NO, CO augments cGMP levels to produce its effects in the brain. Additionally, protein carboxyl methylation and phospholipid methylation involve S-adenosylmethionine acting as the methyl donor. Protein carboxyl methylation and phospholipid methylation are able to impact certain aspects of brain function (i.e., calmodulin-linked enzymes), and indeed both NO and CO have been implicated in long-term neural alterations such as learning and memory. Thus, it has been presumed that these gases could influence events in the nucleus, such as transcription. When released from postsynaptic neurons, these gases have feedback potential that impacts neurotransmitter release, states of neuronal activity, and notably learning and memory.
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