Moss S J, Smart T G, Blackstone C D, Huganir R L
Department of Neuroscience, Howard Hughes Medical Institute, Johns Hopkins University School of Medicine, Baltimore, MD 21205.
Science. 1992 Jul 31;257(5070):661-5. doi: 10.1126/science.1323140.
gamma-Aminobutyric acidA (GABAA) receptors are ligand-gated ion channels that mediate inhibitory synaptic transmission in the central nervous system. The role of protein phosphorylation in the modulation of GABAA receptor function was examined with cells transiently transfected with GABAA receptor subunits. GABAA receptors consisting of the alpha 1 and beta 1 or the alpha 1, beta 1, and gamma 2 subunits were directly phosphorylated on the beta 1 subunit by adenosine 3',5'-monophosphate (cAMP)-dependent protein kinase (PKA). The phosphorylation decreased the amplitude of the GABA response of both receptor types and the extent of rapid desensitization of the GABAA receptor that consisted of the alpha 1 and beta 1 subunits. Site-specific mutagenesis of the serine residue phosphorylated by PKA completely eliminated the PKA phosphorylation and modulation of the GABAA receptor. In primary embryonic rat neuronal cell cultures, a similar regulation of GABAA receptors by PKA was observed. These results demonstrate that the GABAA receptor is directly modulated by protein phosphorylation and suggest that neurotransmitters or neuropeptides that regulate intracellular cAMP levels may modulate the responses of neurons to GABA and consequently have profound effects on synaptic excitability.
γ-氨基丁酸A（GABAA）受体是配体门控离子通道，介导中枢神经系统中的抑制性突触传递。利用瞬时转染了GABAA受体亚基的细胞研究了蛋白质磷酸化在调节GABAA受体功能中的作用。由α1和β1或α1、β1和γ2亚基组成的GABAA受体被3',5'-环磷酸腺苷（cAMP）依赖性蛋白激酶（PKA）直接磷酸化在β1亚基上。这种磷酸化降低了两种受体类型的GABA反应幅度以及由α1和β1亚基组成的GABAA受体的快速脱敏程度。对被PKA磷酸化的丝氨酸残基进行位点特异性诱变完全消除了PKA对GABAA受体的磷酸化和调节作用。在原代胚胎大鼠神经元细胞培养物中，观察到PKA对GABAA受体有类似的调节作用。这些结果表明，GABAA受体直接受蛋白质磷酸化调节，并提示调节细胞内cAMP水平的神经递质或神经肽可能调节神经元对GABA的反应，从而对突触兴奋性产生深远影响。
