Molecular basis of signaling specificity between GIRK channels and GPCRs

Abstract
Data availability
Article and author information
Metrics

Abstract

Stimulated muscarinic acetylcholine receptors (M2Rs) release Gβγ subunits, which slow heart rate by activating a G protein-gated K⁺ channel (GIRK). Stimulated β2 adrenergic receptors (β2ARs) also release Gβγ subunits, but GIRK is not activated. This study addresses the mechanism underlying this specificity of GIRK activation by M2Rs. K⁺ currents and bioluminescence resonance energy transfer between labelled G proteins and GIRK show that M2Rs catalyze Gβγ subunit release at higher rates than β2ARs, generating higher Gβγ concentrations that activate GIRK and regulate other targets of Gβγ. The higher rate of Gβγ release is attributable to a faster G protein coupled receptor - G protein trimer association rate in M2R compared to β2AR. Thus, a rate difference in a single kinetic step accounts for specificity.

Data availability

All data generated or analyzed during this study are included in the manuscript and supporting files.

Article and author information

Author details

Kouki K Touhara

Laboratory of Molecular Neurobiology and Biophysics, Howard Hughes Medical Institute, The Rockefeller University, New York, United States

Competing interests
The authors declare that no competing interests exist.
Roderick MacKinnon

Laboratory of Molecular Neurobiology and Biophysics, Howard Hughes Medical Institute, The Rockefeller University, New York, United States

For correspondence
mackinn@mail.rockefeller.edu

Competing interests
The authors declare that no competing interests exist.

"This ORCID iD identifies the author of this article:" 0000-0001-7605-4679

Funding

National Institutes of Health (GM43949)

Roderick MacKinnon

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Ethics

Animal experimentation: C57BL/6J (Jackson Labs) male and female adult mice (at least 10 weeks old) were used. Animals were kept in cages with a 12 : 12 h light/dark cycle and unrestricted access to food and water. All experimental procedures were carried out according to a protocol approved by the Institutional Animal Care and Use Committee (IACUC) of The Rockefeller University (Protocol #16864).

Copyright

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.