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This Article Full Text Full Text (PDF) Data Supplement All Versions of this Article: 571/1/3    most recent jphysiol.2005.099168v2 jphysiol.2005.099168v1 Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Tammaro, P. Articles by Ashcroft, F. M. Search for Related Content PubMed PubMed Citation Articles by Tammaro, P. Articles by Ashcroft, F. M. Related Collections Molecular and Genomic

¹ University Laboratory of Physiology, Oxford University, Oxford OX1 3PT, UK

ATP-sensitive K⁺ (K_ATP) channels are hetero-octamers of inwardly rectifying K⁺ channel (Kir6.2) and sulphonylurea receptor subunits (SUR1 in pancreatic ß-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 Mg²⁺, both mutations reduced ATP inhibition of SUR1- and SUR2A-containing channels to similar extents, but when Mg²⁺ was present ATP blocked mutant channels containing SUR1 much less than SUR2A channels. Mg-nucleotide activation of SUR1, but not SUR2A, channels was markedly increased by the R201H mutation. Both mutations also increased resting whole-cell K_ATP currents through heterozygous SUR1-containing channels to a greater extent than for heterozygous SUR2A-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 ß-cells but not in the heart.

(Received 22 September 2005; accepted after revision 6 December 2005; first published online 8 December 2005)
Corresponding author F. M. Ashcroft: University Laboratory of Physiology, Parks Road, Oxford OX1 3PT, UK. Email: frances.ashcroft{at}physiol.ox.ac.uk

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