TY - JOUR
T1 - Structural mechanism underlying G protein family-specific regulation of G protein-gated inwardly rectifying potassium channel
AU - Kano, Hanaho
AU - Toyama, Yuki
AU - Imai, Shunsuke
AU - Iwahashi, Yuta
AU - Mase, Yoko
AU - Yokogawa, Mariko
AU - Osawa, Masanori
AU - Shimada, Ichio
N1 - Funding Information:
We thank Mr. Qingci Zhao and Dr. Noritaka Nishida for helping with the culture of HEK293T cells for the BRET assays. The BRET assays were performed at the One-stop Sharing Facility Center for Future Drug Discoveries in the Graduate School of Pharmaceutical Sciences, The University of Tokyo. This work was supported in part by grants from the Japan New Energy and Industrial Technology Development Organization and the Ministry of Economy, Trade, and Industry (to I.S.); Japan Agency for Medical Research and Development (AMED) Grant Number JP18ae010104 (to I.S.); Japan Society for the Promotion of Science (JSPS) KAKENHI Grant Numbers JP17H03978 (to M.O.), JP18H04679 (to M.O.), JP17H06097 (to I.S.), and JP18J13147 (to H.K.); a grant from The Vehicle Racing Commemorative Foundation (to M.O.); and a grant from Takeda Science Foundation (to M.O.).
Publisher Copyright:
© 2019, The Author(s).
PY - 2019/12/1
Y1 - 2019/12/1
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85065195153&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85065195153&partnerID=8YFLogxK
U2 - 10.1038/s41467-019-10038-x
DO - 10.1038/s41467-019-10038-x
M3 - Article
C2 - 31043612
AN - SCOPUS:85065195153
VL - 10
JO - Nature Communications
JF - Nature Communications
SN - 2041-1723
IS - 1
M1 - 2008
ER -