A structural determinant for the control of PIP2 sensitivity in G protein-gated inward rectifier K+ channels.
Inward rectifier K(+) (Kir) channels are activated by phosphatidylinositol-(4,5)-bisphosphate (PIP(2)), but G protein-gated Kir (K(G)) channels further require either G protein βγ subunits (Gβγ) or intracellular Na(+) for their activation. To reveal the mechanism(s) underlying this regulation, we compared the crystal structures of the cytoplasmic domain of K(G) channel subunit Kir3.2 obtained in the presence and the absence of Na(+). The Na(+)-free Kir3.2, but not the Na(+)-plus Kir3.2, possessed an ionic bond connecting the N terminus and the CD loop of the C terminus. Functional analyses revealed that the ionic bond between His-69 on the N terminus and Asp-228 on the CD loop, which are known to be critically involved in Gβγ- and Na(+)-dependent activation, lowered PIP(2) sensitivity. The conservation of these residues within the K(G) channel family indicates that the ionic bond is a character that maintains the channels in a closed state by controlling the PIP(2) sensitivity.
Inanobe
Atsushi
A
Department of Pharmacology, Graduate School of Medicine, Osaka University, Osaka 565-0871, Japan. inanobe@pharma2.med.osaka-u.ac.jp
Nakagawa
Atsushi
A
Matsuura
Takanori
T
Kurachi
Yoshihisa
Y
D000818:Animals; D018360:Crystallography, X-Ray; D051676:G Protein-Coupled Inwardly-Rectifying Potassium Channels / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D051379:Mice; D019269:Phosphatidylinositol 4,5-Diphosphate / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D017433:Protein Structure, Secondary; D017434:Protein Structure, Tertiary; D012964:Sodium / Q000737:chemistry* / Q000378:metabolism; D013329:Structure-Activity Relationship
D051676:G Protein-Coupled Inwardly-Rectifying Potassium Channels; C497069:Kcnj6 protein, mouse; D019269:Phosphatidylinositol 4,5-Diphosphate; D012964:Sodium