Functional effects of naturally occurring KCNJ11 mutations causing neonatal diabetes on cloned cardiac K_(ATP) channels

摘要

ATP-sensitive K~+ (K_(ATP)) channels are hetero-octamers of inwardly rectifying K~+ channel (Kir6.2) and sulphonylurea receptor subunits (SUR1 in pancreatic /3-cells, SUR2A in heart). Heterozygous gain-of-function mutations in Kir6.2 cause neonatal diabetes, which may be accompanied by epilepsy and developmental delay. However, despite the importance of K_(ATP) channels in the heart, patients have no obvious cardiac problems. We examined the effects of adenine nucleotides on K_(ATP) channels containing wild-type or mutant (Q52R, R201H) Kir6.2 plus either SUR1 or SUR2A. In the absence of Mg~(2+), both mutations reduced ATP inhibition of SUR1-and SUR2A-containing channels to similar extents, but when Mg~(2+) was present ATP blocked mutant channels containing SUR1 much less than SUR2A channels. Mg-nucleotide activation of SUR1, but not SUR2 A, channels was mar kedly increased by the R201H mutation. Both mutations also increased resting whole-cell K_(ATP) currents through heterozygous SURl-containing channels to a greater extent than for heterozygous SUR2 A-containing channels. The greater ATP inhibition of mutant Kir6.2/SUR2A than of Kir6.2/SUR1 can explain why gain-of-function Kir6.2 mutations manifest effects in brain and /3-cells but not in the heart.