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Kir6.2 Mutations Associated With Neonatal Diabetes Reduce Expression of ATP-Sensitive K⁺ channels

Implications in Disease Mechanism and Sulfonylurea Therapy

Center for Research on Occupational and Environmental Toxicology, Oregon Health and Science University, Portland, Oregon

Address correspondence and reprint requests to Show-Ling Shyng, Center for Research on Occupational and Environmental Toxicology, Oregon Health and Science University, 3181 SW Sam Jackson Park Rd., Portland, OR 97239. E-mail: shyngs{at}ohsu.edu

Abbreviations: CHOP, CIEBP homolog protein; DEND, developmental delay, epilepsy, and neonatal diabetes; K_ATP channel, ATP-sensitive K⁺ channel; PNDM, permanent neonatal diabetes mellitus; SUR1, sulfonylurea receptor one; UPR, unfolded protein response

Heterozygous missense mutations in the pore-forming subunit Kir6.2 of ATP-sensitive K⁺ channels (K_ATP channels) have recently been shown to cause permanent neonatal diabetes mellitus (PNDM). Functional studies demonstrated that PNDM mutations reduce K_ATP channel sensitivity to ATP inhibition, resulting in gain of channel function. However, the impact of these mutations on channel expression has not been examined. 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 K_ATP 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.

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