Arrhythmia susceptibility and premature death in transgenic mice overexpressing both SUR1 and Kir6.2[ΔN30,K185Q] in the heart

Thomas P. Flagg, Brian Patton, Ricard Masia, Carrie Mansfield, Anatoli N. Lopatin, Kathryn A. Yamada, Colin G. Nichols

Research output: Contribution to journalArticlepeer-review

24 Scopus citations

Abstract

Sarcolemmal ATP-sensitive potassium (KATP) channels are activated after pathological depletion of intracellular ATP, unlike their pancreatic β-cell counterparts, which dynamically regulate membrane excitability in response to changes in blood glucose. We recently engineered a series of transgenic (TG) mice overexpressing an ATP-insensitive inward rectifying K+ channel protein (Kir)6.2 mutant (Kir6.2[ΔN30, K185Q]) or the accessory sulfonylurea receptor (SUR)2A (FLAG-SUR2A) or SUR1 (FLAG-SUR1) subunits of the KATP channel, under transcriptional control of the α-myosin heavy chain promoter. In the present study, we generated double transgenic (DTG) animals overexpressing both Kir6.2[ΔN30,K185Q] and FLAG-SUR1 or FLAG-SUR2A and examined the effects on cardiac excitability in vivo. No animals expressing both FLAG-SUR1 and Kir6.2[ΔN30,K185Q] transgenes at a high level were obtained. DTG mice expressing one transgene at a high level and the other at a lower level are born, but they die prematurely. Electrocardiographic analysis of both anesthetized and conscious animals revealed a constellation of arrhythmias in DTG animals, but not in wild-type or single TG littermates. The proarrhythmic effect of the transgene combination is intrinsic to the myocardium, since it persists in isolated hearts. Importantly, this effect is specific for SUR1-expressing DTG animals: DTG animals expressing both Kir6.2[ΔN30, K185Q] and FLAG-SUR2A at high levels exhibit neither impaired survival nor increased arrhythmia frequency, even with both subunits expressed at high levels. In demonstrating the profound arrhythmic consequences of KATP channels comprised of SUR1 and Kir6.2[ΔN30,K185Q] in the myocardium specifically, the results highlight the critical differential activation of SUR1 versus SUR2A, and indicate that expression of hyperactive KATP in the heart is likely to be proarrhythmic.

Original languageEnglish
Pages (from-to)H836-H845
JournalAmerican Journal of Physiology - Heart and Circulatory Physiology
Volume293
Issue number1
DOIs
StatePublished - Jul 2007

Keywords

  • ATP-sensitive potassium channel
  • Sulfonylurea receptor 2A

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