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Publication : GPCR-dependent biasing of GIRK channel signaling dynamics by RGS6 in mouse sinoatrial nodal cells.

First Author  Anderson A Year  2020
Journal  Proc Natl Acad Sci U S A Volume  117
Issue  25 Pages  14522-14531
PubMed ID  32513692 Mgi Jnum  J:294115
Mgi Id  MGI:6437677 Doi  10.1073/pnas.2001270117
Citation  Anderson A, et al. (2020) GPCR-dependent biasing of GIRK channel signaling dynamics by RGS6 in mouse sinoatrial nodal cells. Proc Natl Acad Sci U S A 117(25):14522-14531
abstractText  How G protein-coupled receptors (GPCRs) evoke specific biological outcomes while utilizing a limited array of G proteins and effectors is poorly understood, particularly in native cell systems. Here, we examined signaling evoked by muscarinic (M2R) and adenosine (A1R) receptor activation in the mouse sinoatrial node (SAN), the cardiac pacemaker. M2R and A1R activate a shared pool of cardiac G protein-gated inwardly rectifying K(+) (GIRK) channels in SAN cells from adult mice, but A1R-GIRK responses are smaller and slower than M2R-GIRK responses. Recordings from mice lacking Regulator of G protein Signaling 6 (RGS6) revealed that RGS6 exerts a GPCR-dependent influence on GIRK-dependent signaling in SAN cells, suppressing M2R-GIRK coupling efficiency and kinetics and A1R-GIRK signaling amplitude. Fast kinetic bioluminescence resonance energy transfer assays in transfected HEK cells showed that RGS6 prefers Galphao over Galphai as a substrate for its catalytic activity and that M2R signals preferentially via Galphao, while A1R does not discriminate between inhibitory G protein isoforms. The impact of atrial/SAN-selective ablation of Galphao or Galphai2 was consistent with these findings. Galphai2 ablation had minimal impact on M2R-GIRK and A1R-GIRK signaling in SAN cells. In contrast, Galphao ablation decreased the amplitude and slowed the kinetics of M2R-GIRK responses, while enhancing the sensitivity and prolonging the deactivation rate of A1R-GIRK signaling. Collectively, our data show that differences in GPCR-G protein coupling preferences, and the Galphao substrate preference of RGS6, shape A1R- and M2R-GIRK signaling dynamics in mouse SAN cells.
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