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Mol Pharmacol. 2017 Dec;92(6):630-639. doi: 10.1124/mol.117.109462. Epub 2017 Sep 27.

Effective Attenuation of Adenosine A1R Signaling by Neurabin Requires Oligomerization of Neurabin.

Author information

1
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.).
2
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.) qinwang@uab.edu.

Abstract

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.

PMID:
28954816
PMCID:
PMC5676298
DOI:
10.1124/mol.117.109462
[Indexed for MEDLINE]
Free PMC Article

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