There is increasing evidence that the cAMP signal transduction system plays key neuromodulatory roles in the central nervous system of vertebrates. Furthermore, cross-talk between signal transduction systems may be particularly important for adaptive changes in neurons and at synapses. Coupling of the Ca2+ and cAMP regulatory systems by the calmodulin regulated adenylyl cyclases is thought to be important for some forms of synaptic plasticity, neuroendocrine function, and sensory detection. In contrast to type I and type 8 adenylyl cyclases, which are stimulated by Ca2+, type 3 adenylyl cyclase (AC3) is strongly activated by Gs-coupled receptors and inhibited by Ca2+. Ca2+ inhibition of AC3 is mediated by CaM kinase II which directly phosphorylates AC3 at Ser-1076 in vivo. This proposal focuses around the hypothesis that the unique regulator properties of AC3 may contribute to cAMP transients observed in some neurons. Since odorant-induced cAMP increases are rapidly followed by elevated intracellular Ca2+, Ca2+ inhibition of AC3 may play a pivotal role in attenuation of cAMP signals caused by odorants. We propose to evaluate this hypothesis using several unique tools developed in this laboratory including AC3 mutant transgenic mice and a peptide-specific antibody for the CaM kinase II phosphorylation site within AC3. This study should provide fundamental information concerning the role of AC3 and CaM kinase II for generation of cAMP transients in neurons.
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