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Here, we show that PNDM mutations, including Q52R, V59G, V59M, R201C, R201H, and I296L, not only reduce channel ATP sensitivity but also impair channel expression at the cell surface to varying degrees. By tagging the PNDM Kir6.2 mutant V59G or R201H with an additional mutation, N160D, that confers voltage-dependent polyamine block of KATP channels, we demonstrate that in simulated heterozygous state, all surface channels are either wild-type or heteromeric channels containing both wild-type and mutant Kir6.2 subunits. Comparison of the various PNDM mutations in their effects on channel nucleotide sensitivity and expression, as well as disease phenotype, suggests that both channel-gating defect and expression level may play a role in determining disease severity. Interestingly, sulfonylureas significantly increase surface expression of certain PNDM mutants, suggesting that the efficacy of sulfonylurea therapy may be compromised by the effect of these drugs on channel expression.<\/jats:p>","DOI":"10.2337\/db05-1571","type":"journal-article","created":{"date-parts":[[2006,5,26]],"date-time":"2006-05-26T20:00:23Z","timestamp":1148673623000},"page":"1738-1746","update-policy":"https:\/\/doi.org\/10.2337\/ada-journal-policies","source":"Crossref","is-referenced-by-count":39,"title":["Kir6.2 Mutations Associated With Neonatal Diabetes Reduce Expression of ATP-Sensitive K+ channels"],"prefix":"10.2337","volume":"55","author":[{"given":"Chia-Wei","family":"Lin","sequence":"first","affiliation":[{"name":"Center for Research on Occupational and Environmental Toxicology, Oregon Health and Science University, Portland, Oregon"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yu-Wen","family":"Lin","sequence":"additional","affiliation":[{"name":"Center for Research on Occupational and Environmental Toxicology, Oregon Health and Science University, Portland, Oregon"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Fei-Fei","family":"Yan","sequence":"additional","affiliation":[{"name":"Center for Research on Occupational and Environmental Toxicology, Oregon Health and Science University, Portland, Oregon"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jillene","family":"Casey","sequence":"additional","affiliation":[{"name":"Center for Research on Occupational and Environmental Toxicology, Oregon Health and Science University, Portland, Oregon"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Malini","family":"Kochhar","sequence":"additional","affiliation":[{"name":"Center for Research on Occupational and Environmental Toxicology, Oregon Health and Science University, Portland, Oregon"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Emily B.","family":"Pratt","sequence":"additional","affiliation":[{"name":"Center for Research on Occupational and Environmental Toxicology, Oregon Health and Science University, Portland, Oregon"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Show-Ling","family":"Shyng","sequence":"additional","affiliation":[{"name":"Center for Research on Occupational and Environmental Toxicology, Oregon Health and Science University, Portland, Oregon"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1167","reference":[{"key":"2022031210152677800_R1","doi-asserted-by":"crossref","unstructured":"Aguilar-Bryan L, Bryan J: Molecular biology of adenosine triphosphate-sensitive potassium channels. 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