Functional effects of <it>KCNJ11</it> mutations causing neonatal diabetes: enhanced activation by MgATP

Authors: Proks, Peter; Girard, Christophe; Ashcroft, Frances M.

Source: Human Molecular Genetics, Volume 14, Number 18, 15 September 2005 , pp. 2717-2726(10)

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Abstract:

Recent studies have shown that heterozygous mutations in KCNJ11, which encodes Kir6.2, the pore-forming subunit of the ATP-sensitive potassium (K<inf>ATP</inf>) channel, cause permanent neonatal diabetes either alone (R201C, R201H) or in association with developmental delay, muscle weakness and epilepsy (V59G,V59M). Functional analysis in the absence of Mg²⁺, to isolate the inhibitory effects of ATP on Kir6.2, showed that both types of mutation reduce channel inhibition by ATP. However, in pancreatic beta

-cells, K<inf>ATP</inf> channel activity is governed by the balance between ATP inhibition via Kir6.2 and Mg-nucleotide stimulation mediated by an auxiliary subunit, the sulphonylurea receptor SUR1. We therefore studied the MgATP sensitivity of KCNJ11 mutant K<inf>ATP</inf> channels expressed in Xenopus oocytes. In contrast to wild-type channels, Mg²⁺ dramatically reduced the ATP sensitivity of heterozygous R201C, R201H, V59M and V59G channels. This effect was predominantly mediated via the nucleotide-binding domains of SUR1 and resulted from an enhanced stimulatory action of MgATP. Our results therefore demonstrate that KCNJ11 mutations increase the current magnitude of heterozygous K<inf>ATP</inf> channels in two ways: by increasing MgATP activation and by decreasing ATP inhibition. They further show that the fraction of unblocked K<inf>ATP</inf> current at physiological MgATP concentrations correlates with the severity of the clinical phenotype.

Keywords: communicable disease; influenza; mumps; salmonella; disease management; bloodborne viruses; chemical incidents; emergency preparedness

Document Type: Research article

DOI: http://dx.doi.org/10.1093/hmg/ddi305

Affiliations: 1: To whom correspondence should be addressed. frances.ashcroft@physiol.ox.ac.uk, Tel: +44 1865285810, Fax: +44 1865285812

Publication date: 2005-09-15

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