Cyclic AMP-dependent protein kinase phosphorylation facilitates GABAB receptor-effector coupling
Cyclic AMP-dependent protein kinase phosphorylation facilitates GABAB receptor-effector coupling
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DOI：
10.1038/nn833
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发表时间：
2002-05-01
影响因子：
25
通讯作者：
Moss, SJ
中科院分区：
文献类型：
--
作者：
Couve, A;Thomas, P;Moss, SJ
GABA(氨基丁酸)(B)受体是一种异二聚体G蛋白偶联受体，在中枢神经系统中介导缓慢的突触抑制。在这里，我们发现GABA(B)R1/GABA(B)R2受体与内向整流K(+)通道的功能偶联迅速减敏。通过cAMP(CAMP)依赖的蛋白激酶(PKA)直接磷酸化GABA(B)R2胞浆尾部的单个丝氨酸残基(Ser892)后，这种影响被减轻。这种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的磷酸化受升高cAMP浓度的途径的正向调节，例如涉及Forsklin和β-肾上腺素能受体的途径。GABA(B)受体激动剂减少受体磷酸化，这与PKA在控制GABA(B)激活电流方面的功能是一致的。从机制上讲，Ser892的磷酸化特异性地增强了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的影响。这些结果也挑战了公认的观点，即磷酸化是G蛋白偶联受体的普遍负调节因子。
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.