GABAB receptor phosphorylation regulates KCTD12-induced K⁺ current desensitization.
GABAB receptor phosphorylation regulates KCTD12-induced K⁺ current desensitization.
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DOI：
10.1016/j.bcp.2014.07.013
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发表时间：
2014-10-01
影响因子：
5.8
通讯作者：
Bettler, Bernhard
中科院分区：
文献类型：
--
作者：
Adelfinger, Lisa;Turecek, Rostislav;Ivankova, Klara;Jensen, Anders A.;Moss, Stephen J.;Gassmann, Martin;Bettler, Bernhard
GABAB受体由GABAB 1和GABAB 2亚基组装而成。GABAB 2还与辅助KCTD亚基（以其K+通道四聚化结构域命名）相关。GABAB受体与异源三聚体G蛋白偶联，并通过从G蛋白释放的βγ亚基激活内向整流K+通道。受体激活的K+电流在激动剂的持续存在下脱敏，以避免对神经元活性的过度影响。K+电流的脱敏整合了不同的机制基础。GABAB受体活性降低蛋白激酶-A活性，蛋白激酶-A活性降低GABAB 2中丝氨酸-892的磷酸化并促进受体降解。这种形式的脱敏在几分钟到几小时的时间尺度上运作。辅助亚基KCTD 12诱导了一种更快的脱敏形式，它通过与G蛋白βγ亚基结合来干扰通道激活。在这里，我们表明，这两种机制的脱敏相互影响。丝氨酸-892磷酸化在异源细胞重排KCTD 12的受体和减缓KCTD 12诱导的脱敏。同样，海马神经元中的蛋白激酶A激活减慢GABAB受体激活的K+电流的快速脱敏，而蛋白激酶A抑制加速快速脱敏。蛋白激酶-A不能调节KCTD 12敲除小鼠或具有丝氨酸-892至丙氨酸突变的敲入小鼠的快速脱敏，从而证明丝氨酸-892磷酸化调节KCTD 12诱导的体内脱敏。快电流脱敏在携带丝氨酸-892到丙氨酸突变的海马神经元中加速，表明强直性丝氨酸-892磷酸化通常限制KCTD 12诱导的脱敏。紧张性丝氨酸-892磷酸化反过来通过与KCTD 12的受体组装而促进。这种丝氨酸-892磷酸化和KCTD 12活性的交叉调节在重复的受体活化期间使反应尖锐化。
GABAB receptors assemble from GABAB1 and GABAB2 subunits. GABAB2 additionally associates with auxiliary KCTD subunits (named after their K+ channel tetramerization-domain). GABAB receptors couple to heterotrimeric G–proteins and activate inwardly-rectifying K+ channels through the βγ subunits released from the G-protein. Receptor-activated K+ currents desensitize in the sustained presence of agonist to avoid excessive effects on neuronal activity. Desensitization of K+ currents integrates distinct mechanistic underpinnings. GABAB receptor activity reduces protein kinase-A activity, which reduces phosphorylation of serine-892 in GABAB2 and promotes receptor degradation. This form of desensitization operates on the time scale of several minutes to hours. A faster form of desensitization is induced by the auxiliary subunit KCTD12, which interferes with channel activation by binding to the G-protein βγ subunits. Here we show that the two mechanisms of desensitization influence each other. Serine-892 phosphorylation in heterologous cells rearranges KCTD12 at the receptor and slows KCTD12-induced desensitization. Likewise, protein kinase-A activation in hippocampal neurons slows fast desensitization of GABAB receptor-activated K+ currents while protein kinase-A inhibition accelerates fast desensitization. Protein kinase-A fails to regulate fast desensitization in KCTD12 knock-out mice or knock-in mice with a serine-892 to alanine mutation, thus demonstrating that serine-892 phosphorylation regulates KCTD12-induced desensitization in vivo. Fast current desensitization is accelerated in hippocampal neurons carrying the serine-892 to alanine mutation, showing that tonic serine-892 phosphorylation normally limits KCTD12-induced desensitization. Tonic serine-892 phosphorylation is in turn promoted by assembly of receptors with KCTD12. This cross-regulation of serine-892 phosphorylation and KCTD12 activity sharpens the response during repeated receptor activation.
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