Structural mechanism underlying G protein family-specific regulation of G protein-gated inwardly rectifying potassium channel

Hanaho Kano, Yuki Toyama, Shunsuke Imai, Yuta Iwahashi, Yoko Mase, Mariko Yokogawa, Masanori Osawa and Ichio Shimada ()
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Hanaho Kano: The University of Tokyo
Yuki Toyama: The University of Tokyo
Shunsuke Imai: The University of Tokyo
Yuta Iwahashi: The University of Tokyo
Yoko Mase: The University of Tokyo
Mariko Yokogawa: The University of Tokyo
Masanori Osawa: The University of Tokyo
Ichio Shimada: The University of Tokyo

Nature Communications, 2019, vol. 10, issue 1, 1-13

Abstract: Abstract G protein-gated inwardly rectifying potassium channel (GIRK) plays a key role in regulating neurotransmission. GIRK is opened by the direct binding of the G protein βγ subunit (Gβγ), which is released from the heterotrimeric G protein (Gαβγ) upon the activation of G protein-coupled receptors (GPCRs). GIRK contributes to precise cellular responses by specifically and efficiently responding to the Gi/o-coupled GPCRs. However, the detailed mechanisms underlying this family-specific and efficient activation are largely unknown. Here, we investigate the structural mechanism underlying the Gi/o family-specific activation of GIRK, by combining cell-based BRET experiments and NMR analyses in a reconstituted membrane environment. We show that the interaction formed by the αA helix of Gαi/o mediates the formation of the Gαi/oβγ-GIRK complex, which is responsible for the family-specific activation of GIRK. We also present a model structure of the Gαi/oβγ-GIRK complex, which provides the molecular basis underlying the specific and efficient regulation of GIRK.

Date: 2019
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DOI: 10.1038/s41467-019-10038-x

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