Proceedings of The Physiological Society

University of Oxford (2011) Proc Physiol Soc 23, PC263

Poster Communications

Mice expressing a human KATP channel mutation have altered channel ATP sensitivity, but no cardiac abnormalities

R. Mannikko1, R. Clark1, D. Stuckey1, M. Iberl1, K. Clarke1, F. M. Ashcroft1

1. Department of Physiology Anatomy & Genetics, University of Oxford, Oxford, United Kingdom.

Patients with severe gain-of-function mutations in Kir6.2 (KCNJ11), the pore-forming subunit of the ATP-sensitive potassium (KATP) channel, have neonatal diabetes, muscle flaccidity, and mental and motor developmental delay; a condition known as iDEND syndrome. Despite the fact that Kir6.2 forms the pore of the cardiac KATP channel and is abundantly expressed in the heart, the patients show no obvious cardiac symptoms. We used a mouse model of iDEND syndrome to determine if the lack of cardiac symptoms is because iDEND mutations do not alter ATP inhibition of the cardiac channel. We studied mice in which the most common iDEND mutation (Kir6.2-V59M) was targeted to cardiac muscle using Cre-lox technology (m-V59M mice). Quantitative rtPCR revealed that wild-type and mutant mRNAs were expressed at about the same level in the heart of m-V59M mice, indicating that m-V59M mice simulate the heterozygous state of the patients. Patch-clamp studies of isolated cardiac myocytes revealed a marked reduction in the sensitivity of the KATP channel in m-V59M mice to MgATP inhibition (IC50 = 62 µM compared to 13 µM for littermate controls). In vivo cine MRI of mice anesthetized with 1.5% isoflurane in O2 identified no gross morphological differences and no differences in heart rate, end diastolic volume, end systolic volume, stroke volume, ejection fraction, cardiac output or wall thickening between m-V59M and control hearts, either under resting conditions or under dobutamine stress. In summary, the common iDEND mutation Kir6.2-V59M decreases ATP block of cardiac KATP channels but is without effect on heart function. This suggests that metabolic changes fail to open the mutated channel to an extent that affects function. In contrast, when the Kir6.2-V59M mutation is expressed in pancreatic beta-cells, mice fail to secrete insulin. It is likely these different effects on cell function result from differences in the SUR subunit of the channel (SUR1 in beta-cells; SUR2A in heart).

Where applicable, experiments conform with Society ethical requirements