{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,5]],"date-time":"2026-10-05T15:43:48Z","timestamp":1791215028893,"version":"4.1.0"},"reference-count":41,"publisher":"Rockefeller University Press","issue":"2","content-domain":{"domain":["rupress.org"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[1999,8,1]]},"abstract":"<jats:p>The sensitivity of KATP 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 KATP 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 KATP channels (Kir6.2[\u0394N30] or Kir6.2[L164A], coexpressed with SUR1) also displayed an \u201cuncoupled\u201d 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 \u201cuncoupling\u201d 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.<\/jats:p>","DOI":"10.1085\/jgp.114.2.203","type":"journal-article","created":{"date-parts":[[2002,7,26]],"date-time":"2002-07-26T16:50:20Z","timestamp":1027702220000},"page":"203-213","update-policy":"https:\/\/doi.org\/10.1085\/jgp.crossmarkpolicy","source":"Crossref","is-referenced-by-count":81,"title":["Sulfonylurea and K+-Channel Opener Sensitivity of KATP Channels"],"prefix":"10.1085","volume":"114","author":[{"given":"J.C.","family":"Koster","sequence":"first","affiliation":[{"name":"aFrom the Department of Cell Biology and Physiology, Washington University School of Medicine, St. Louis, Missouri 63110"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Q.","family":"Sha","sequence":"additional","affiliation":[{"name":"aFrom the Department of Cell Biology and Physiology, Washington University School of Medicine, St. Louis, Missouri 63110"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"C.G.","family":"Nichols","sequence":"additional","affiliation":[{"name":"aFrom the Department of Cell Biology and Physiology, Washington University School of Medicine, St. Louis, Missouri 63110"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"291","published-online":{"date-parts":[[1999,8,1]]},"reference":[{"key":"2023072918105530600_Aguilar-Bryanetal1995","doi-asserted-by":"crossref","first-page":"423","DOI":"10.1126\/science.7716547","article-title":"The \u03b2 cell high affinity sulfonylurea receptora regulator of insulin secretion","volume":"268","author":"Aguilar-Bryan","year":"1995","journal-title":"Science."},{"key":"2023072918105530600_Ashcroft1988","doi-asserted-by":"crossref","first-page":"97","DOI":"10.1146\/annurev.ne.11.030188.000525","article-title":"Adenosine 5\u2032-triphosphate-sensitive potassium channels","volume":"11","author":"Ashcroft","year":"1988","journal-title":"Annu. 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