Molecular basis of signaling specificity between GIRK channels and GPCRs
- Howard Hughes Medical Institute, The Rockefeller University, United States
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
Roderick MacKinnon
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
© 2018, Touhara & MacKinnon
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.
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Molecular basis of signaling specificity between GIRK channels and GPCRs
eLife 7:e42908.
https://doi.org/10.7554/eLife.42908
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