Dataset Information

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 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 G?_o over G?_i as a substrate for its catalytic activity and that M₂R signals preferentially via G?_o, while A₁R does not discriminate between inhibitory G protein isoforms. The impact of atrial/SAN-selective ablation of G?_o or G?_i2 was consistent with these findings. G?_i2 ablation had minimal impact on M₂R-GIRK and A₁R-GIRK signaling in SAN cells. In contrast, G?_o 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 G?_o substrate preference of RGS6, shape A₁R- and M₂R-GIRK signaling dynamics in mouse SAN cells.

SUBMITTER: Anderson A

PROVIDER: S-EPMC7322085 | biostudies-literature | 2020 Jun

REPOSITORIES: biostudies-literature

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

Anderson Allison A Masuho Ikuo I Marron Fernandez de Velasco Ezequiel E Nakano Atsushi A Birnbaumer Lutz L Martemyanov Kirill A KA Wickman Kevin K

Proceedings of the National Academy of Sciences of the United States of America 20200608 25

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) chann ...[more]

PMID: 32513692

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Project description:Background and objectiveThe sinoatrial nodal artery (SANa) is a highly variable vessel which supplies blood to the sinoatrial node (SAN). Due to its variability and susceptibility to iatrogenic injury, our study aimed to assess the anatomy of the SANa and determine the prevalence of its anatomical variations.Study designAn extensive search of major electronic databases was performed to identify all articles reporting anatomical data on the SANa. No lower date limit or language restrictions were applied. Anatomical data regarding the artery were extracted and pooled into a meta-analysis.ResultsSixty-six studies (n = 21455 hearts) were included in the meta-analysis. The SANa usually arose as a single vessel with a pooled prevalence of 95.5% (95%CI:93.6-96.9). Duplication and triplication of the artery were also observed with pooled prevalence of 4.3% (95%CI:2.8-6.0) and 0.3% (95%CI:0-0.7), respectively. The most common origin of the SANa was from the right coronary artery (RCA), found in 68.0% (95%CI:55.6-68.9) of cases, followed by origin from the left circumflex artery, and origin from the left coronary artery with pooled prevalence of 22.1% (95%CI:15.0-26.2) and 2.7 (95%CI:0.7-5.2), respectively. A retrocaval course of the SANa was the most common course of the artery with a pooled prevalence of 47.1% (95%CI:36.0-55.5). The pooled prevalence of an S-shaped SANa was 7.6% (95%CI:2.9-14.1).ConclusionsThe SANa is most commonly reported as a single vessel, originating from the RCA, and taking a retrocaval course to reach the SAN. Knowledge of high risk anatomical variants of the SANa, such as an S-shaped artery, must be taken into account by surgeons to prevent iatrogenic injuries. Specifically, interventional or cardiosurgical procedures, such as the Cox maze procedure for atrial fibrillation, open heart surgeries through the right atrium or intraoperative cross-clamping or dissection procedures during mitral valve surgery using the septal approach can all potentiate the risk for injury in the setting of high-risk morphological variants of the SANa.

Dataset Information

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

Publications

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

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