Interactions between Neurotransmitters that Regulate cAMP and Intracellular Ca2+ Levels in the CNS
Two major second messenger signalling systems play prominent roles in the regulation of neuronal activity — that which modulates intracellular cAMP levels and that which results in an elevation in intracellular Ca2+ concentrations. Intracellular Ca2+ is now known to be mobilized as a consequence of receptor modulation of inositol phosphate metabolism.1 It is widely recognised that both of these pathways can lead to changes in the level of intracellular protein phosphorylation through the mediation of distinct protein kinases -sometimes converging on a single target protein, as is the situation in the case of tyrosine hydroxylase.2 However, less widely recognized is the fact that these signalling systems also interact more immediately at the level of the generation of their rimary signals. Recent studies — for instance those by Jakobs et al3 — indicate that, in some cells, the Ca2+-activated, protein kinase C, eliminates hormone inhibition of adenylate cyclase which is mediated by inhibitory GTP regulatory elements. It has also been recognised for some time that Ca2+/calmodulin regulates a specific cyclic AMP phosphodiesterase in neuronal tissue; this interaction provides a mechanism whereby Ca2+ signals can decrease cAMP levels.4,5 Thus, the potential for interaction between systems that utilize Ca2+ and cAMP has already been established. In order to explore other potential mechanisms by which these two systems interact at the level of signal generation, recent studies from these laboratories have focussed on two major issues: 1) additional functions that may be served by putative “cyclase-inhibitory” receptors in the CNS. The physiological significance of adenylate cyclase inhibition in neuronal tissue has often been questioned, since the magnitude of the effect is so modest -rarely exceeding 25%. In the present studies additional functions supported by “cyclase inhibitory” receptors are investigated; and, 2) the impact of Ca2+-signals on the regulation of adenylate cyclase by cyclase-linked receptors. Over the past few years, a focus in one of these laboratories ha been the fact — first reported by Brostrom et al.6 — that Ca2+/calmodulin can regulate neuronal adenylate cyclase — particularly in terms of its implications for neurotransmitter regulation of adenylate cyclase. Initial studies on the hippocampal system had indicated that adenosine-Al receptor-mediated inhibition of adenylate cyclase could occur only upon Ca2+/calmodulin stimulation of activity.7 Current studies have attempted to determine how widespread this phenomenon is within the nervous system, whether it applies to all inhibitory neurotransmitters8,9 and the implications of this regulation for stimulatory neurotransmission.
KeywordsAdenylate Cyclase Pertussis Toxin Inositol Phosphate Adenylate Cyclase Activity Adenosine Analogue
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