title: Distant cytosolic residues mediate a two-way molecular switch that controls the modulation of inwardly rectifying potassium (Kir) channels by cholesterol and phosphatidylinositol 4,5-bisphosphate (PI(4,5)P(2)).
abstract: BACKGROUND
  Cholesterol modulates inwardly rectifying potassium (Kir) channels.
  
  
  RESULTS
  A two-way molecular cytosolic switch controls channel modulation by cholesterol and PI(4,5)P(2).
  
  
  CONCLUSIONS
  Cholesterol and PI(4,5)P(2) induce a common gating pathway of Kir2.1 despite their opposite impact on channel function.
  
  
  CONCLUSIONS
  These findings provide insights into structure-function relationship of ion channels and contribute to understanding of the mechanisms underlying their regulation by lipids. Inwardly rectifying potassium (Kir) channels play an important role in setting the resting membrane potential and modulating membrane excitability. An emerging feature of several Kir channels is that they are regulated by cholesterol. However, the mechanism by which cholesterol affects channel function is unclear. Here we show that mutations of two distant Kir2.1 cytosolic residues, Leu-222 and Asn-251, form a two-way molecular switch that controls channel modulation by cholesterol and affects critical hydrogen bonding. Notably, these two residues are linked by a residue chain that continues from Asn-251 to connect adjacent subunits. Furthermore, our data indicate that the same switch also regulates the sensitivity of the channels to phosphatidylinositol 4,5-bisphosphate, a phosphoinositide that is required for activation of Kir channels. Thus, although cholesterol and phosphatidylinositol 4,5-bisphosphate do not interact with the same region of Kir2.1, these different modulators induce a common gating pathway of the channel.
authors.affiliation: Department of Medicine, Pulmonary Section, University of Illinois, Chicago, IL 60612, USA. dantsker@uic.edu
authors.forename: Avia
authors.initials: A
authors.lastname: Rosenhouse-Dantsker
authors.forename: Sergei
authors.initials: S
authors.lastname: Noskov
authors.forename: Huazhi
authors.initials: H
authors.lastname: Han
authors.forename: Scott K
authors.initials: SK
authors.lastname: Adney
authors.forename: Qiong-Yao
authors.initials: QY
authors.lastname: Tang
authors.forename: Aldo A
authors.initials: AA
authors.lastname: Rodríguez-Menchaca
authors.forename: Gregory B
authors.initials: GB
authors.lastname: Kowalsky
authors.forename: Vasileios I
authors.initials: VI
authors.lastname: Petrou
authors.forename: Catherine V
authors.initials: CV
authors.lastname: Osborn
authors.forename: Diomedes E
authors.initials: DE
authors.lastname: Logothetis
authors.forename: Irena
authors.initials: I
authors.lastname: Levitan
mesh_terms: D020816:Amino Acid Motifs; D000595:Amino Acid Sequence; D000818:Animals; D002784:Cholesterol / Q000378:metabolism*; D057809:HEK293 Cells; D006801:Humans; D008969:Molecular Sequence Data; D009154:Mutation; D009865:Oocytes / Q000378:metabolism; D019269:Phosphatidylinositol 4,5-Diphosphate / Q000378:metabolism*; D024661:Potassium Channels, Inwardly Rectifying / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D014981:Xenopus
chemical_list: C489461:Kir2.1 channel; C489463:Kir2.2 channel; D019269:Phosphatidylinositol 4,5-Diphosphate; D024661:Potassium Channels, Inwardly Rectifying; D002784:Cholesterol