Orphan Receptor GPR158 is an Allosteric Modulator of Regulator of G Protein Signaling 7 (RGS7) Catalytic Activity with Essential Role in Dictating its Expression and Localization in the Brain [Neurobiology]

March 19th, 2015 by Orlandi, C., Xie, K., Masuho, I., Fajardo-Serrano, A., Lujan, R., Martemyanov, K. A.

Regulators of G protein Signaling (RGS) 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 membrane proteins RGS7 Binding Protein (R7BP) or orphan receptor GPR158. In this study we examine the impact of GPR158 on RGS7 in the brain. We report that knockout 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 RGS7 binding site in the C-terminus of GPR158 and found that it shares significant homology with R7BP. The proximal portion of GPR158 C-terminus additionally contained a conserved sequence that was capable of enhancing RGS7 GAP activity in solution by an allosteric mechanism acting in conjunction with the RGS-binding domain. The distal portion of the GPR158 C-terminus contained several PDE╬│-Like (PGL) 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 critical role in controlling its expression, membrane localization and catalytic activity.
  • Posted in Journal of Biological Chemistry, Publications
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