Couve A, Thomas P, Calver A R, Hirst W D, Pangalos M N, Walsh F S, Smart T G, Moss S J
Medical Research Council Laboratory of Molecular Cell Biology and Department of Pharmacology, University College London, Gower Street, London WC1E 6BT, UK.
Nat Neurosci. 2002 May;5(5):415-24. doi: 10.1038/nn833.
GABA (gamma-aminobutyric acid)(B) receptors are heterodimeric G protein-coupled receptors that mediate slow synaptic inhibition in the central nervous system. Here we show that the functional coupling of GABA(B)R1/GABA(B)R2 receptors to inwardly rectifying K(+) channels rapidly desensitizes. This effect is alleviated after direct phosphorylation of a single serine residue (Ser892) in the cytoplasmic tail of GABA(B)R2 by cyclic AMP (cAMP)-dependent protein kinase (PKA). Basal phosphorylation of this residue is evident in rat brain membranes and in cultured neurons. Phosphorylation of Ser892 is modulated positively by pathways that elevate cAMP concentration, such as those involving forskolin and beta-adrenergic receptors. GABA(B) receptor agonists reduce receptor phosphorylation, which is consistent with PKA functioning in the control of GABA(B)-activated currents. Mechanistically, phosphorylation of Ser892 specifically enhances the membrane stability of GABA(B) receptors. We conclude that signaling pathways that activate PKA may have profound effects on GABA(B) receptor-mediated synaptic inhibition. These results also challenge the accepted view that phosphorylation is a universal negative modulator of G protein-coupled receptors.
γ-氨基丁酸（GABA）（B）受体是异二聚体G蛋白偶联受体，介导中枢神经系统中的慢突触抑制。我们在此表明，GABA（B）R1/GABA（B）R2受体与内向整流钾通道的功能偶联会迅速脱敏。环磷酸腺苷（cAMP）依赖性蛋白激酶（PKA）直接磷酸化GABA（B）R2胞质尾部的单个丝氨酸残基（Ser892）后，这种效应会得到缓解。该残基的基础磷酸化在大鼠脑膜和培养的神经元中很明显。Ser892的磷酸化受到提高cAMP浓度的信号通路的正向调节，例如涉及福斯可林和β-肾上腺素能受体的信号通路。GABA（B）受体激动剂会降低受体磷酸化，这与PKA在控制GABA（B）激活电流中的作用一致。从机制上讲，Ser892的磷酸化特异性增强了GABA（B）受体的膜稳定性。我们得出结论，激活PKA的信号通路可能对GABA（B）受体介导的突触抑制有深远影响。这些结果也挑战了普遍认为磷酸化是G蛋白偶联受体的普遍负性调节剂的观点。
