TY - JOUR
T1 - Effective attenuation of adenosine a1r signaling by neurabin requires oligomerization of neurabin
AU - Chen, Yunjia
AU - Booth, Christopher
AU - Wang, Hongxia
AU - Wang, Raymond X.
AU - Terzi, Dimitra
AU - Zachariou, Venetia
AU - Jiao, Kai
AU - Zhang, Jin
AU - Wang, Qin
N1 - Publisher Copyright:
© 2017 by The American Society for Pharmacology and Experimental Therapeutics.
PY - 2017/12
Y1 - 2017/12
N2 - 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 plasmamembrane, 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.
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 plasmamembrane, 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.
UR - http://www.scopus.com/inward/record.url?scp=85034451568&partnerID=8YFLogxK
U2 - 10.1124/mol.117.109462
DO - 10.1124/mol.117.109462
M3 - Article
C2 - 28954816
AN - SCOPUS:85034451568
SN - 0026-895X
VL - 92
SP - 630
EP - 639
JO - Molecular Pharmacology
JF - Molecular Pharmacology
IS - 6
ER -