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Original Article

Functional Coupling of Kir6.2 and Sur1 Subunits

J.C. Koster^a, Q. Sha^a, and C.G. Nichols^a

^a From the Department of Cell Biology and Physiology, Washington University School of Medicine, St. Louis, Missouri 63110
Department of Cell Biology and Physiology, Washington University School of Medicine, 660 South Euclid Avenue, St. Louis, MO 63110.Fax: 314-362-7463;

cnichols{at}cellbio.wustl.edu

The sensitivity of K_ATP channels to high-affinity block by sulfonylureas and to stimulation by K⁺ channel openers and MgADP (PCOs) is conferred by the regulatory sulfonylurea receptor (SUR) subunit, whereas ATP inhibits the channel through interaction with the inward rectifier (Kir6.2) subunit. Phosphatidylinositol 4,5-bisphosphate (PIP₂) profoundly antagonized ATP inhibition of K_ATP channels expressed from cloned Kir6.2+SUR1 subunits, but also abolished high affinity tolbutamide sensitivity. By stabilizing the open state of the channel, PIP₂ drives the channel away from closed state(s) that are preferentially affected by high affinity tolbutamide binding, thereby producing an apparent loss of high affinity tolbutamide inhibition. Mutant K_ATP channels (Kir6.2[N30] or Kir6.2[L164A], coexpressed with SUR1) also displayed an "uncoupled" phenotype with no high affinity tolbutamide block and with intrinsically higher open state stability. Conversely, Kir6.2[R176A]+SUR1 channels, which have an intrinsically lower open state stability, displayed a greater high affinity fraction of tolbutamide block. In addition to antagonizing high-affinity block by tolbutamide, PIP₂ also altered the stimulatory action of the PCOs, diazoxide and MgADP. With time after PIP₂ application, PCO stimulation first increased, and then subsequently decreased, probably reflecting a common pathway for activation of the channel by stimulatory PCOs and PIP₂. The net effect of increasing open state stability, either by PIP₂ or mutagenesis, is an apparent "uncoupling" of the Kir6.2 subunit from the regulatory input of SUR1, an action that can be partially reversed by screening negative charges on the membrane with poly-L-lysine.

Key Words: K⁺ current • sulfonylurea • MgADP • diazoxide • PIP₂

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