REGULATION OF CAMP TRANSIENTS IN NEURONS

描述：（申请人摘要） 越来越多的证据表明，cAMP信号转导系统起着关键作用， 在脊椎动物中枢神经系统中的神经调节作用。 此外，信号转导系统之间的串扰可能特别重要。 对神经元和突触的适应性变化很重要。Ca 2+的耦合 和cAMP调节系统的钙调素调节腺苷酸环化酶， 神经内分泌被认为对某些形式的突触可塑性很重要， 功能和感官检测。与I型和8型腺苷酸相反， 腺苷酸环化酶3型（AC 3）是一种由Ca 2+刺激的环化酶， 受Gs偶联受体的强烈激活和Ca ~（2+）的抑制。Ca2+ AC 3的抑制由CaM激酶II介导，其直接磷酸化 体内AC 3的Ser-1076。这一建议的重点是假设， AC 3的独特调节特性可能有助于观察到的cAMP瞬变 在一些神经元中。由于气味诱导的cAMP增加迅速， 细胞内Ca ~（2+）升高，AC 3的Ca ~（2+）抑制可能在 由气味剂引起的cAMP信号衰减。我们建议评估这一点 使用该实验室开发的几种独特工具进行假设，包括 AC 3突变转基因小鼠和CaM激酶的肽特异性抗体 AC 3内的II磷酸化位点。这项研究将提供基本的 关于AC 3和CaM激酶II在产生cAMP中的作用的信息 神经元中的瞬变。

DESCRIPTION: (Applicant's Abstract) 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.