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Structural Basis for Modulation of Gating Property of G Protein-gated Inwardly Rectifying Potassium Ion Channel (GIRK) by i/o-family G Protein α Subunit (Gαi/o)

The Journal of biological chemistry, 2012-06, Vol.287 (23), p.19537-19549 [Peer Reviewed Journal]

2012 © 2012 ASBMB. Currently published by Elsevier Inc; originally published by American Society for Biochemistry and Molecular Biology. ;2012 by The American Society for Biochemistry and Molecular Biology, Inc. 2012 ;ISSN: 0021-9258 ;EISSN: 1083-351X ;DOI: 10.1074/jbc.M112.353888 ;PMID: 22511772

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Title:
Structural Basis for Modulation of Gating Property of G Protein-gated Inwardly Rectifying Potassium Ion Channel (GIRK) by i/o-family G Protein α Subunit (Gαi/o)
Author: Mase, Yoko ; Yokogawa, Mariko ; Osawa, Masanori ; Shimada, Ichio
Subjects: Animals ; G Protein Signaling ; G Protein α Subunit ; G Protein-Coupled Inwardly-Rectifying Potassium Channels - chemistry ; G Protein-Coupled Inwardly-Rectifying Potassium Channels - genetics ; G Protein-Coupled Inwardly-Rectifying Potassium Channels - metabolism ; GIRK ; GTP-Binding Protein alpha Subunits, Gi-Go - chemistry ; GTP-Binding Protein alpha Subunits, Gi-Go - genetics ; GTP-Binding Protein alpha Subunits, Gi-Go - metabolism ; Heterotrimeric G Proteins ; Mice ; Models, Molecular ; NMR ; Nuclear Magnetic Resonance, Biomolecular ; Potassium Channels ; Protein Structure, Quaternary ; Protein Structure, Secondary ; Protein Structure, Tertiary ; Protein-Protein Interactions ; Signal Transduction ; Structure-Activity Relationship
Is Part Of: The Journal of biological chemistry, 2012-06, Vol.287 (23), p.19537-19549
Description: G protein-gated inwardly rectifying potassium channel (GIRK) plays a crucial role in regulating heart rate and neuronal excitability. The gating of GIRK is regulated by the association and dissociation of G protein βγ subunits (Gβγ), which are released from pertussis toxin-sensitive G protein α subunit (Gαi/o) upon GPCR activation in vivo. Several lines of evidence indicate that Gαi/o also interacts directly with GIRK, playing functional roles in the signaling efficiency and the modulation of the channel activity. However, the underlying mechanism for GIRK regulation by Gαi/o remains to be elucidated. Here, we performed NMR analyses of the interaction between the cytoplasmic region of GIRK1 and Gαi3 in the GTP-bound state. The NMR spectral changes of Gα upon the addition of GIRK as well as the transferred cross-saturation (TCS) results indicated their direct binding mode, where the Kd value was estimated as ∼1 mm. The TCS experiments identified the direct binding sites on Gα and GIRK as the α2/α3 helices on the GTPase domain of Gα and the αA helix of GIRK. In addition, the TCS and paramagnetic relaxation enhancement results suggested that the helical domain of Gα transiently interacts with the αA helix of GIRK. Based on these results, we built a docking model of Gα and GIRK, suggesting the molecular basis for efficient GIRK deactivation by Gαi/o. Although Gβγ is known to activate GIRK, Gαi/o also modulates GIRK gating. The α2/α3 helices of Gαi3 in the GTP-bound state directly bind to the αA helix of GIRK. The complex model explains how Gαi/o sequesters Gβγ efficiently from GIRK upon GTP hydrolysis. The structural basis for the rapid closure of GIRK by Gαi/o is provided.
Publisher: United States: Elsevier Inc
Language: English
Identifier: ISSN: 0021-9258
EISSN: 1083-351X
DOI: 10.1074/jbc.M112.353888
PMID: 22511772
Source: MEDLINE
PubMed Central
Alma/SFX Local Collection

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Structural Basis for Modulation of Gating Property of G Protein-gated Inwardly Rectifying Potassium Ion Channel (GIRK) by i/o-family G Protein α Subunit (Gαi/o)

2012 © 2012 ASBMB. Currently published by Elsevier Inc; originally published by American Society for Biochemistry and Molecular Biology. ;2012 by The American Society for Biochemistry and Molecular Biology, Inc. 2012 ;ISSN: 0021-9258 ;EISSN: 1083-351X ;DOI: 10.1074/jbc.M112.353888 ;PMID: 22511772

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