Chen Yunjia, Booth Christopher, Wang Hongxia, Wang Raymond X, Terzi Dimitra, Zachariou Venetia, Jiao Kai, Zhang Jin, Wang Qin
Departments of Cell, Developmental, and Integrative Biology (Y.C., H.W., R.X.W., Q.W.) and Genetics (K.J.), University of Alabama, Birmingham, Alabama; Department of Pharmacology, University of California, San Diego, California (C.B., J.Z.); and Department of Neuroscience, Friedman Brain Institute, Mount Sinai School of Medicine, New York, New York (D.T., V.Z.).
Departments of Cell, Developmental, and Integrative Biology (Y.C., H.W., R.X.W., Q.W.) and Genetics (K.J.), University of Alabama, Birmingham, Alabama; Department of Pharmacology, University of California, San Diego, California (C.B., J.Z.); and Department of Neuroscience, Friedman Brain Institute, Mount Sinai School of Medicine, New York, New York (D.T., V.Z.)
Mol Pharmacol. 2017 Dec;92(6):630-639. doi: 10.1124/mol.117.109462. Epub 2017 Sep 27.
The adenosine A1 receptor (A1R) is a key mediator of the neuroprotective effect by endogenous adenosine. Yet targeting this receptor for neuroprotection is challenging due to its broad expression throughout the body. A mechanistic understanding of the regulation of A1R signaling is necessary for the future design of therapeutic agents that can selectively enhance A1R-mediated responses in the nervous system. In this study, we demonstrate that A1R activation leads to a sustained localization of regulator of G protein signaling 4 (RGS4) at the plasma membrane, a process that requires neurabin (a neural tissue-specific protein). A1R and RGS4 interact with the overlapping regions of neurabin. In addition, neurabin domains required for oligomerization are essential for formation of the A1R/neurabin/RGS4 ternary complex, as well as for stable localization of RGS4 at the plasma membrane and attenuation of A1R signaling. Thus, A1R and RGS4 each likely interact with one neurabin molecule in a neurabin homo-oligomer to form a ternary complex, representing a novel mode of regulation of G protein-coupled receptor signaling by scaffolding proteins. Our mechanistic analysis of neurabin-mediated regulation of A1R signaling in this study will be valuable for the future design of therapeutic agents that can selectively enhance A1R-mediated responses in the nervous system.
腺苷A1受体（A1R）是内源性腺苷发挥神经保护作用的关键介质。然而，由于A1R在全身广泛表达，将该受体作为神经保护靶点具有挑战性。对于能够选择性增强A1R在神经系统中介导反应的治疗药物的未来设计而言，对A1R信号调节机制的理解是必要的。在本研究中，我们证明A1R激活导致G蛋白信号调节因子4（RGS4）在质膜上持续定位，这一过程需要神经素（一种神经组织特异性蛋白）。A1R和RGS4与神经素的重叠区域相互作用。此外，神经素寡聚化所需的结构域对于A1R/神经素/RGS4三元复合物的形成、RGS4在质膜上的稳定定位以及A1R信号的减弱至关重要。因此，A1R和RGS4可能各自在神经素同型寡聚体中与一个神经素分子相互作用，形成三元复合物，这代表了支架蛋白对G蛋白偶联受体信号进行调节的一种新模式。我们在本研究中对神经素介导的A1R信号调节的机制分析，对于未来设计能够选择性增强A1R在神经系统中介导反应的治疗药物将具有重要价值。
