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。 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 对神经元和突触的适应性变化很重要。钙离子的偶联 而cAMP调节系统由钙调蛋白调控的腺酰环化酶是 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型腺苷形成对比 受钙离子刺激的环化酶，3型腺酰环化酶(AC3)是 受Gs偶联受体强烈激活，受钙离子抑制。Ca2+ AC3的抑制是由直接磷酸化的CaM激酶II介导的 AC3在体内的Ser-1076。这一提议主要围绕这样一种假设： AC3独特的调节特性可能有助于观察到的cAMP瞬变 在一些神经元中。由于气味引起的cAMP增加很快就会 细胞内钙升高，钙离子抑制AC3可能在脑出血中起关键作用 气味引起的cAMP信号衰减。我们建议对此进行评估 使用本实验室开发的几个独特工具进行假设，包括 AC3突变型转基因小鼠及CaM蛋白的多肽特异性抗体 II AC3内的磷酸化位点。这项研究应该提供基本的 AC3和CaM激酶II在cAMP生成中作用的研究进展 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.