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

Abstract: 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 activati...

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Autores principales: Anderson, Allison, Masuho, Ikuo, Marrón Fernández de Velasco, Ezequiel, Nakano, Atsushi, Birnbaumer, Lutz, Martemyanov, Kirill A., Wickman, Kevin
Formato: Artículo
Lenguaje:Inglés
Publicado: National Academy of Sciences 2022
Materias:
RITMO CARDIACO
Kir3
ADENOSINA
Acceso en línea:https://repositorio.uca.edu.ar/handle/123456789/14237
Aporte de:
Repositorio Institucional de la Universidad Católica Argentina (UCA) de Universidad Católica Argentina
id I33-R139-123456789-14237
record_format dspace
institution Universidad Católica Argentina
institution_str I-33
repository_str R-139
collection Repositorio Institucional de la Universidad Católica Argentina (UCA)
language Inglés
topic RITMO CARDIACO
Kir3
ADENOSINA
spellingShingle RITMO CARDIACO
Kir3
ADENOSINA
Anderson, Allison
Masuho, Ikuo
Marrón Fernández de Velasco, Ezequiel
Nakano, Atsushi
Birnbaumer, Lutz
Martemyanov, Kirill A.
Wickman, Kevin
GPCR-dependent biasing of GIRK channel signaling dynamics by RGS6 in mouse sinoatrial nodal cells
topic_facet RITMO CARDIACO
Kir3
ADENOSINA
description Abstract: 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 GPCRdependent 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 Gαo over Gαi as a substrate for its catalytic activity and that M2R signals preferentially via Gαo, while A1R does not discriminate between inhibitory G protein isoforms. The impact of atrial/SAN-selective ablation of Gαo or Gαi2 was consistent with these findings. Gαi2 ablation hadminimal impact onM2R-GIRK and A1R-GIRK signaling in SAN cells. In contrast, Gαo 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 Gαo substrate preference of RGS6, shape A1R- and M2R-GIRK signaling dynamics in mouse SAN cells.
format Artículo
author Anderson, Allison
Masuho, Ikuo
Marrón Fernández de Velasco, Ezequiel
Nakano, Atsushi
Birnbaumer, Lutz
Martemyanov, Kirill A.
Wickman, Kevin
author_facet Anderson, Allison
Masuho, Ikuo
Marrón Fernández de Velasco, Ezequiel
Nakano, Atsushi
Birnbaumer, Lutz
Martemyanov, Kirill A.
Wickman, Kevin
author_sort Anderson, Allison
title GPCR-dependent biasing of GIRK channel signaling dynamics by RGS6 in mouse sinoatrial nodal cells
title_short GPCR-dependent biasing of GIRK channel signaling dynamics by RGS6 in mouse sinoatrial nodal cells
title_full GPCR-dependent biasing of GIRK channel signaling dynamics by RGS6 in mouse sinoatrial nodal cells
title_fullStr GPCR-dependent biasing of GIRK channel signaling dynamics by RGS6 in mouse sinoatrial nodal cells
title_full_unstemmed GPCR-dependent biasing of GIRK channel signaling dynamics by RGS6 in mouse sinoatrial nodal cells
title_sort gpcr-dependent biasing of girk channel signaling dynamics by rgs6 in mouse sinoatrial nodal cells
publisher National Academy of Sciences
publishDate 2022
url https://repositorio.uca.edu.ar/handle/123456789/14237
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