Orphan Receptor GPR158 Is an Allosteric Modulator of RGS7 Catalytic Activity with an Essential Role in Dictating Its Expression and Localization in the Brain
Orphan Receptor GPR158 Is an Allosteric Modulator of RGS7 Catalytic Activity with an Essential Role in Dictating Its Expression and Localization in the Brain
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DOI：
10.1074/jbc.m115.645374
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发表时间：
2015-05-29
影响因子：
4.8
通讯作者：
Martemyanov, Kirill A.
中科院分区：
文献类型：
--
作者：
Orlandi, Cesare;Xie, Keqiang;Martemyanov, Kirill A.
G蛋白信号调节因子通过加速G蛋白α亚基上的GTP水解，从而促进GPCR信号的终止，从而通过G蛋白偶联受体（GPCR）途径控制信号传导的持续时间和程度。该家族的一员RGS7在神经系统中起着关键作用，它调节多种神经递质gpcr，介导视觉、记忆和成瘾药物的作用。已有研究证实，体内RGS7与膜蛋白RGS7结合蛋白或孤儿受体GPR158形成互斥复合物。在这项研究中，我们研究了GPR158对大脑中RGS7的影响。我们报道，在小鼠中敲除GPR158会导致RGS7的显著转录后不稳定，并且在几个脑区域中RGS7与膜的关联显著丧失。我们进一步在GPR158的C端鉴定了rgs7结合位点，发现其与rgs7结合蛋白具有显著的同源性。GPR158 C末端的近端部分还包含一个保守序列，该序列能够通过与G蛋白信号结合域的调节因子共同作用的变弹性机制增强RGS7 gtpase激活蛋白在溶液中的活性。GPR158 C末端的远端部分含有几个磷酸二酯酶E - γ样基序，并选择性地招募处于激活状态的G蛋白。本研究结果证实GPR158是天然神经系统中RGS7的重要调节因子，在控制RGS7的表达、膜定位和催化活性方面发挥着关键作用。
Regulators of G protein signaling control the duration and extent of signaling via G protein-coupled receptor (GPCR) pathways by accelerating the GTP hydrolysis on G protein alpha subunits thereby promoting termination of GPCR signaling. A member of this family, RGS7, plays a critical role in the nervous system where it regulates multiple neurotransmitter GPCRs that mediate vision, memory, and the action of addictive drugs. Previous studies have established that in vivo RGS7 forms mutually exclusive complexes with the membrane protein RGS7-binding protein or the orphan receptor GPR158. In this study, we examine the impact of GPR158 on RGS7 in the brain. We report that knock-out of GPR158 in mice results in marked post-transcriptional destabilization of RGS7 and substantial loss of its association with membranes in several brain regions. We further identified the RGS7-binding site in the C terminus of GPR158 and found that it shares significant homology with the RGS7-binding protein. The proximal portion of the GPR158 C terminus additionally contained a conserved sequence that was capable of enhancing RGS7 GTPase-activating protein activity in solution by an allosteric mechanism acting in conjunction with the regulators of the G protein signaling-binding domain. The distal portion of the GPR158 C terminus contained several phosphodiesterase E gamma-like motifs and selectively recruited G proteins in their activated state. The results of this study establish GPR158 as an essential regulator of RGS7 in the native nervous system with a critical role in controlling its expression, membrane localization, and catalytic activity.