{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,18]],"date-time":"2026-08-18T14:40:48Z","timestamp":1787064048212,"version":"build-2736575974"},"reference-count":30,"publisher":"Rockefeller University Press","issue":"7","license":[{"start":{"date-parts":[[2019,1,2]],"date-time":"2019-01-02T00:00:00Z","timestamp":1546387200000},"content-version":"vor","delay-in-days":218,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc-sa\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000062","name":"National Institute of Diabetes and Digestive and Kidney Diseases","doi-asserted-by":"publisher","award":["DK109979"],"award-info":[{"award-number":["DK109979"]}],"id":[{"id":"10.13039\/100000062","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["rupress.org"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2018,7,2]]},"abstract":"<jats:p>The adenosine triphosphate (ATP)-sensitive (KATP) channels in pancreatic \u03b2 cells couple the blood glucose level to insulin secretion. KATP channels in pancreatic \u03b2 cells comprise the pore-forming Kir6.2 and the modulatory sulfonylurea receptor 1 (SUR1) subunits. Currently, there is no high-affinity and relatively specific inhibitor for the Kir6.2 pore. The importance of developing such inhibitors is twofold. First, in many cases, the lack of such an inhibitor precludes an unambiguous determination of the Kir6.2's role in certain physiological and pathological processes. This problem is exacerbated because Kir6.2 knockout mice do not yield the expected phenotypes of hyperinsulinemia and hypoglycemia, which in part, may reflect developmental adaptation. Second, mutations in Kir6.2 or SUR1 that increase the KATP current cause permanent neonatal diabetes mellitus (PNDM). Many patients who have PNDM have been successfully treated with sulphonylureas, a common class of antidiabetic drugs that bind to SUR1 and indirectly inhibit Kir6.2, thereby promoting insulin secretion. However, some PNDM-causing mutations render KATP channels insensitive to sulphonylureas. Conceptually, because these mutations are located intracellularly, an inhibitor blocking the Kir6.2 pore from the extracellular side might provide another approach to this problem. Here, by screening the venoms from &amp;gt;200 animals against human Kir6.2 coexpressed with SUR1, we discovered a small protein of 54 residues (SpTx-1) that inhibits the KATP channel from the extracellular side. It inhibits the channel with a dissociation constant value of 15 nM in a relatively specific manner and with an apparent one-to-one stoichiometry. SpTx-1 evidently inhibits the channel by primarily targeting Kir6.2 rather than SUR1; it inhibits not only wild-type Kir6.2 coexpressed with SUR1 but also a Kir6.2 mutant expressed without SUR1. Importantly, SpTx-1 suppresses both sulfonylurea-sensitive and -insensitive, PNDM-causing Kir6.2 mutants. Thus, it will be a valuable tool to investigate the channel's physiological and biophysical properties and to test a new strategy for treating sulfonylurea-resistant PNDM.<\/jats:p>","DOI":"10.1085\/jgp.201812017","type":"journal-article","created":{"date-parts":[[2018,5,29]],"date-time":"2018-05-29T16:15:16Z","timestamp":1527610516000},"page":"969-976","update-policy":"https:\/\/doi.org\/10.1085\/jgp.crossmarkpolicy","source":"Crossref","is-referenced-by-count":17,"title":["A novel high-affinity inhibitor against the human ATP-sensitive Kir6.2 channel"],"prefix":"10.1085","volume":"150","author":[{"given":"Yajamana","family":"Ramu","sequence":"first","affiliation":[{"name":"Department of Physiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yanping","family":"Xu","sequence":"additional","affiliation":[{"name":"Department of Physiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7108-9303","authenticated-orcid":true,"given":"Zhe","family":"Lu","sequence":"additional","affiliation":[{"name":"Department of Physiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"291","published-online":{"date-parts":[[2018,5,29]]},"reference":[{"key":"2023072705253373700_bib1","doi-asserted-by":"publisher","first-page":"423","DOI":"10.1126\/science.7716547","article-title":"Cloning of the beta cell high-affinity sulfonylurea receptor: A regulator of insulin secretion","volume":"268","author":"Aguilar-Bryan","year":"1995","journal-title":"Science."},{"key":"2023072705253373700_bib2","doi-asserted-by":"publisher","first-page":"S62","DOI":"10.2337\/dc11-S062","article-title":"Diagnosis and classification of diabetes mellitus","volume":"34","author":"American Diabetes Association","year":"2011","journal-title":"Diabetes Care."},{"key":"2023072705253373700_bib3","doi-asserted-by":"publisher","first-page":"2047","DOI":"10.1172\/JCI25495","article-title":"ATP-sensitive potassium channelopathies: focus on insulin secretion","volume":"115","author":"Ashcroft","year":"2005","journal-title":"J. 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