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This Article Full Text Full Text (PDF) All Versions of this Article: 293/1/H836    most recent 00011.2007v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in ISI Web of Science 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 Flagg, T. P. Articles by Nichols, C. G. Search for Related Content PubMed PubMed Citation Articles by Flagg, T. P. Articles by Nichols, C. G.

Arrhythmia susceptibility and premature death in transgenic mice overexpressing both SUR1 and Kir6.2[N30,K185Q] in the heart

¹Department of Cell Biology and Physiology and ²Department of Medicine, Washington University School of Medicine, St. Louis, Missouri; and ³Department of Physiology, University of Michigan Medical School, Ann Arbor, Michigan

Submitted 4 January 2007 ; accepted in final form 3 April 2007

Sarcolemmal ATP-sensitive potassium (K_ATP) channels are activated after pathological depletion of intracellular ATP, unlike their pancreatic -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[N30,K185Q]) or the accessory sulfonylurea receptor (SUR)2A (FLAG-SUR2A) or SUR1 (FLAG-SUR1) subunits of the K_ATP channel, under transcriptional control of the -myosin heavy chain promoter. In the present study, we generated double transgenic (DTG) animals overexpressing both Kir6.2[N30,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[N30,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[N30,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 K_ATP channels comprised of SUR1 and Kir6.2[N30,K185Q] in the myocardium specifically, the results highlight the critical differential activation of SUR1 versus SUR2A, and indicate that expression of hyperactive K_ATP in the heart is likely to be proarrhythmic.

ATP-sensitive potassium channel; sulfonylurea receptor 2A

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				T. P. Flagg, H. T. Kurata, R. Masia, G. Caputa, M. A. Magnuson, D. J. Lefer, W. A. Coetzee, and C. G. Nichols Differential Structure of Atrial and Ventricular KATP: Atrial KATP Channels Require SUR1 Circ. Res., December 5, 2008; 103(12): 1458 - 1465. [Abstract] [Full Text] [PDF]