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Molecular basis of signaling specificity between GIRK channels and GPCRs.

ABSTRACT: Stimulated muscarinic acetylcholine receptors (M2Rs) release G?? subunits, which slow heart rate by activating a G protein-gated K+ channel (GIRK). Stimulated ?2 adrenergic receptors (?2ARs) also release G?? 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 G?? subunit release at higher rates than ?2ARs, generating higher G?? concentrations that activate GIRK and regulate other targets of G??. The higher rate of G?? release is attributable to a faster G protein coupled receptor - G protein trimer association rate in M2R compared to ?2AR. Thus, a rate difference in a single kinetic step accounts for specificity.

SUBMITTER: Touhara KK

PROVIDER: S-EPMC6335053 | biostudies-literature | 2018 Dec

REPOSITORIES: biostudies-literature

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Molecular basis of signaling specificity between GIRK channels and GPCRs.

Touhara Kouki K KK MacKinnon Roderick R

eLife 20181210

Stimulated muscarinic acetylcholine receptors (M2Rs) release Gβγ subunits, which slow heart rate by activating a G protein-gated K<sup>+</sup> 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<sup>+</sup> currents and bioluminescence resonance energy transfer between labelled G proteins and GIRK show that M2Rs catalyze Gβγ subunit release at ...[more]

PMID: 30526853

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