HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text Full Text (PDF) All Versions of this Article: 286/4/H1361    most recent 00676.2003v1 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 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 Web of Science (13) Citing Articles via Google Scholar Google Scholar Articles by Flagg, T. P. Articles by Nichols, C. Search for Related Content PubMed PubMed Citation Articles by Flagg, T. P. Articles by Nichols, C.

Remodeling of excitation-contraction coupling in transgenic mice expressing ATP-insensitive sarcolemmal K_ATP channels

¹Department of Cell Biology and Physiology, Washington University School of Medicine, St. Louis, Missouri 63110; ²Institut National de la Santé et de la Recherche Médicale Unitè 533, Physiopathologie et Pharmacologie Cellulaires et Moléculaires, Faculté de Médecine, 44035 Nantes, France; ³Department of Physiology, University of Michigan Medical School, Ann Arbor, Michigan 48109; and ⁴Department of Pharmacology, University of Alberta, Edmonton T6G 2H7, Alberta, Canada

Submitted 25 July 2003 ; accepted in final form 2 December 2003

Reducing the ATP sensitivity of the sarcolemmal ATP-sensitive K⁺ (K_ATP) channel is predicted to lead to active channels in normal metabolic conditions and hence cause shortened ventricular action potentials and reduced myocardial inotropy. We generated transgenic (TG) mice that express an ATP-insensitive K_ATP channel mutant [Kir6.2(N2–30,K185Q)] under transcriptional control of the -myosin heavy chain promoter. Strikingly, myocyte contraction amplitude was increased in TG myocytes (15.68 ± 1.15% vs. 10.96 ± 1.49%), even though K_ATP channels in TG myocytes are very insensitive to inhibitory ATP. Under normal metabolic conditions, steady-state outward K⁺ currents measured under whole cell voltage clamp were elevated in TG myocytes, consistent with threshold K_ATP activation, but neither the monophasic action potential measured in isolated hearts nor transmembrane action potential measured in right ventricular muscle preparations were shortened at physiological pacing cycles. Taken together, these results suggest that there is a compensatory remodeling of excitation-contraction coupling in TG myocytes. Whereas there were no obvious differences in other K⁺ conductances, peak L-type Ca²⁺ current (I_Ca) density (–16.42 ± 2.37 pA/pF) in the TG was increased compared with the wild type (–8.43 ± 1.01 pA/pF). Isoproterenol approximately doubled both I_Ca and contraction amplitude in wild-type myocytes but failed to induce a significant increase in TG myocytes. Baseline and isoproterenol-stimulated cAMP concentrations were not different in wild-type and TG hearts, suggesting that the enhancement of I_Ca in the latter does not result from elevated cAMP. Collectively, the data demonstrate that a compensatory increase in I_Ca counteracts a mild activation of ATP-insensitive K_ATP channels to maintain the action potential duration and elevate the inotropic state of TG hearts.

ATP-sensitive K⁺ channels; contractility; action potential

This article has been cited by other articles:

				P. J. Schaeffer, J. DeSantiago, J. Yang, T. P. Flagg, A. Kovacs, C. J. Weinheimer, M. Courtois, T. C. Leone, C. G. Nichols, D. M. Bers, et al. Impaired contractile function and calcium handling in hearts of cardiac-specific calcineurin b1-deficient mice Am J Physiol Heart Circ Physiol, October 1, 2009; 297(4): H1263 - H1273. [Abstract] [Full Text] [PDF]

				T. P. Flagg, O. Cazorla, M. S. Remedi, T. E. Haim, M. A. Tones, A. Bahinski, R. E. Numann, A. Kovacs, J. E. Schaffer, C. G. Nichols, et al. Ca2+-Independent Alterations in Diastolic Sarcomere Length and Relaxation Kinetics in a Mouse Model of Lipotoxic Diabetic Cardiomyopathy Circ. Res., January 2, 2009; 104(1): 95 - 103. [Abstract] [Full Text] [PDF]

				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]

				T. P. Flagg, B. Patton, R. Masia, C. Mansfield, A. N. Lopatin, K. A. Yamada, and C. G. Nichols Arrhythmia susceptibility and premature death in transgenic mice overexpressing both SUR1 and Kir6.2[{Delta}N30,K185Q] in the heart Am J Physiol Heart Circ Physiol, July 1, 2007; 293(1): H836 - H845. [Abstract] [Full Text] [PDF]

				X. Tong, L. M. Porter, G. Liu, P. Dhar-Chowdhury, S. Srivastava, D. J. Pountney, H. Yoshida, M. Artman, G. I. Fishman, C. Yu, et al. Consequences of cardiac myocyte-specific ablation of KATP channels in transgenic mice expressing dominant negative Kir6 subunits Am J Physiol Heart Circ Physiol, August 1, 2006; 291(2): H543 - H551. [Abstract] [Full Text] [PDF]