Geller A I, During M J, Haycock J W, Freese A, Neve R
Division of Endocrinology, Children's Hospital, Boston, MA 02115.
Proc Natl Acad Sci U S A. 1993 Aug 15;90(16):7603-7. doi: 10.1073/pnas.90.16.7603.
Signal-transduction pathways mediate a wide range of short-term changes in the physiology of neuronal systems from invertebrates to mammals. However, examples of long-term changes in neuronal physiology mediated by these pathways have been limited to invertebrate systems. In this report, long-term changes in the physiology of mammalian neurons were studied by using genetic intervention to cause a long-lasting activation of the cAMP pathway. The catalytic domain of yeast adenylate cyclase (cyr), encoding a constitutive enzyme activity, was expressed in neuronal cells infected with a defective herpes simplex virus vector (pHSVcyr). In PC-12 cells infected with pHSVcyr, increases were seen in cAMP levels, protein kinase A activity, protein phosphorylation, phosphorylation of the tyrosine hydroxylase protein kinase A site (Ser40), and catecholamine release. Infection of sympathetic neurons with pHSVcyr increased cAMP levels, protein phosphorylation, and catecholamine release. Yeast adenylate cyclase immunoreactivity and elevated cAMP levels were localized to the cell bodies of sympathetic neurons. The increase in neurotransmitter release was both Ca(2+)- and activity-dependent and persisted for at least 1 week after infection of the sympathetic neurons, suggesting that sustained physiological activation of the cAMP pathway may mediate long-term changes in the neuronal physiology of mammalian systems.
信号转导通路介导了从无脊椎动物到哺乳动物的神经元系统生理过程中的广泛短期变化。然而，由这些通路介导的神经元生理长期变化的例子仅限于无脊椎动物系统。在本报告中，通过基因干预使cAMP通路长期激活，研究了哺乳动物神经元生理的长期变化。编码组成型酶活性的酵母腺苷酸环化酶（cyr）的催化结构域，在感染有缺陷单纯疱疹病毒载体（pHSVcyr）的神经元细胞中表达。在感染pHSVcyr的PC-12细胞中，观察到cAMP水平、蛋白激酶A活性、蛋白质磷酸化、酪氨酸羟化酶蛋白激酶A位点（Ser40）的磷酸化以及儿茶酚胺释放增加。用pHSVcyr感染交感神经元会增加cAMP水平、蛋白质磷酸化和儿茶酚胺释放。酵母腺苷酸环化酶免疫反应性和升高的cAMP水平定位于交感神经元的细胞体。神经递质释放的增加是Ca(2+)依赖性和活性依赖性的，并且在交感神经元感染后至少持续1周，这表明cAMP通路的持续生理激活可能介导哺乳动物系统神经元生理的长期变化。
