title: Specificity of activation by phosphoinositides determines lipid regulation of Kir channels.
abstract: Phosphoinositides are critical regulators of ion channel and transporter activity. Defects in interactions of inwardly rectifying potassium (Kir) channels with phosphoinositides lead to disease. ATP-sensitive K(+) channels (K(ATP)) are unique among Kir channels in that they serve as metabolic sensors, inhibited by ATP while stimulated by long-chain (LC) acyl-CoA. Here we show that K(ATP) are the least specific Kir channels in their activation by phosphoinositides and we demonstrate that LC acyl-CoA activation of these channels depends on their low phosphoinositide specificity. We provide a systematic characterization of phosphoinositide specificity of the entire Kir channel family expressed in Xenopus oocytes and identify molecular determinants of such specificity. We show that mutations in the Kir2.1 channel decreasing phosphoinositide specificity allow activation by LC acyl-CoA. Our data demonstrate that differences in phosphoinositide specificity determine the modulation of Kir channel activity by distinct regulatory lipids.
authors.affiliation: Department of Physiology and Biophysics, Mount Sinai School of Medicine of New York University, New York, NY 10029, USA.
authors.forename: Tibor
authors.initials: T
authors.lastname: Rohács
authors.forename: Coeli M B
authors.initials: CM
authors.lastname: Lopes
authors.forename: Taihao
authors.initials: T
authors.lastname: Jin
authors.forename: Pavan P
authors.initials: PP
authors.lastname: Ramdya
authors.forename: Zoltán
authors.initials: Z
authors.lastname: Molnár
authors.forename: Diomedes E
authors.initials: DE
authors.lastname: Logothetis
mesh_terms: D000214:Acyl Coenzyme A / Q000494:pharmacology; D000595:Amino Acid Sequence; D000818:Animals; D051676:G Protein-Coupled Inwardly-Rectifying Potassium Channels; D006801:Humans; D008969:Molecular Sequence Data; D010716:Phosphatidylinositols / Q000494:pharmacology*; D015221:Potassium Channels / Q000737:chemistry / Q000187:drug effects* / Q000502:physiology; D024661:Potassium Channels, Inwardly Rectifying / Q000187:drug effects / Q000502:physiology; D014981:Xenopus
chemical_list: D000214:Acyl Coenzyme A; D051676:G Protein-Coupled Inwardly-Rectifying Potassium Channels; D010716:Phosphatidylinositols; D015221:Potassium Channels; D024661:Potassium Channels, Inwardly Rectifying; C017585:oleoyl-coenzyme A