A sodium-mediated structural switch that controls the sensitivity of Kir channels to PtdIns(4,5)P(2).
Inwardly rectifying potassium (Kir) channels are gated by the membrane phospholipid phosphatidylinositol-4,5-bisphosphate (PtdIns(4,5)P(2)). Among them, Kir3 requires additional molecules, such as the betagamma subunits of G proteins or intracellular sodium, for channel gating. Using an interactive computational-experimental approach, we show that sodium sensitivity of Kir channels involves the side chains of an aspartate and a histidine located across from each other in a crucial loop in the cytosolic domain, as well as the backbone carbonyls of two more residues and a water molecule. The location of the coordination site in the vicinity of a conserved arginine shown to affect channel-PtdIns(4,5)P(2) interactions suggests that sodium triggers a structural switch that frees the crucial arginine. Mutations of the aspartate and the histidine that affect sodium sensitivity also enhance the channel's sensitivity to PtdIns(4,5)P(2). Furthermore, on the basis of the molecular characteristics of the coordination site, we identify and confirm experimentally a sodium-sensitive phenotype in Kir5.1.
Rosenhouse-Dantsker
Avia
A
Department of Structural and Chemical Biology, Mount Sinai School of Medicine, One Gustave L. Levy Place, New York, New York 10029, USA.
Sui
Jin L
JL
Zhao
Qi
Q
Rusinova
Radda
R
Rodríguez-Menchaca
Aldo A
AA
Zhang
Zhe
Z
Logothetis
Diomedes E
DE
D000595:Amino Acid Sequence; D003198:Computer Simulation; D051676:G Protein-Coupled Inwardly-Rectifying Potassium Channels / Q000737:chemistry / Q000187:drug effects / Q000378:metabolism*; D015640:Ion Channel Gating / Q000187:drug effects / Q000502:physiology*; D007477:Ions / Q000737:chemistry / Q000378:metabolism; D008958:Models, Molecular; D008969:Molecular Sequence Data; D019269:Phosphatidylinositol 4,5-Diphosphate / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology; D016415:Sequence Alignment; D012964:Sodium / Q000737:chemistry / Q000378:metabolism*
D051676:G Protein-Coupled Inwardly-Rectifying Potassium Channels; D007477:Ions; D019269:Phosphatidylinositol 4,5-Diphosphate; D012964:Sodium
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