The Role of Cyclic Nucleotides in the Nervous System

Abstract

A wide variety of roles have been suggested for cyclic nucleotides in both the central and peripheral nervous systems. Cyclic AMP has been hypothesized to be the intracellular second messenger for a variety of inhibitory transmitters, most notably norepinephrine, dopamine, and serotonin. In addition, cyclic GMP has been suggested to mediate the effects of acetylcholine and glutamate. While this “second messenger” role of cyclic nucleotides is perhaps most well known, there are indications that they serve a variety of other functions as well. Cyclic AMP appears to be involved in the modulation of the postsynaptic responsiveness of several transmitter systems; adenosine, which can raise cyclic AMP levels by itself, appears implicated in many of these effects. Cyclic nucleotides have also been suggested as being either directly involved in exocytosis, or affecting the release of transmitter indirectly via a regulatory action on release processes. Cyclic nucleotides appear to act by activating a class of cyclic AMP and cyclic GMP-dependent protein kinases. While the functions of some of the endogenous substrates for these kinases, and the effect of phosphorylation are largely unknown, in some cases (e.g., phosphorylation of tyrosine hydroxylase) the physiological significance of the phosphorylated and dephosphorylated states of the protein are quite clear. In the case of tyrosine hydroxylase, cyclic AMP certainly does not appear to be functioning as a second messenger to mediate the physiological effects of a neurotransmitter, but instead to be mediating a more complex type of regulatory effect. Glial cells also have cyclic nucleotide generating systems; while their functions is somewhat unclear, there are indications that changes in cyclic AMP in glial cells may influence intermediary metabolism in the brain. In terms of behavior, it is difficult to summarize the interrelationships between cyclic nucleotides and behavioral responses, particularly in animals with well-developed and therefore complex nervous systems. It would appear that cyclic nucleotide levels are affected under certain conditions, such as during epileptic activity or possibly in affective disorders. However, it is not clear whether the alterations in cyclic nucleotides are directly involved in the etiology of these conditions, or vice versa.