RT Journal Article SR Electronic T1 Effective Attenuation of Adenosine A1R Signaling by Neurabin Requires Oligomerization of Neurabin JF Molecular Pharmacology JO Mol Pharmacol FD American Society for Pharmacology and Experimental Therapeutics SP 630 OP 639 DO 10.1124/mol.117.109462 VO 92 IS 6 A1 Yunjia Chen A1 Christopher Booth A1 Hongxia Wang A1 Raymond X. Wang A1 Dimitra Terzi A1 Venetia Zachariou A1 Kai Jiao A1 Jin Zhang A1 Qin Wang YR 2017 UL http://molpharm.aspetjournals.org/content/92/6/630.abstract AB 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.