J Mol Cell Cardiol 33, 249–259 (2001) doi:10.1006/jmcc.2000.1296, available online at http://www.idealibrary.com on Enhanced Ca 2+ Channel Currents in Cardiac Hypertrophy Induced by Activation of Calcineurin-dependent Pathway Atsuko Yatani 1 , Ritsu Honda 1 , Kevin M. Tymitz 2 , M. Jane Lalli 1 and Jeffery D. Molkentin 2 1 Department of Pharmacology and Cell Biophysics, University of Cincinnati College of Medicine and 2 Division of Molecular Cardiovascular Biology, Children’s Hospital Medical Center, Cincinnati, OH, USA (Received 25 August 2000, accepted in revised form 6 November 2000, published electronically 18 December 2000) A. Y , R. H, K. M. T, M. J. L J. D. M. Enhanced Ca 2+ Channel Currents in Cardiac Hypertrophy Induced by Activation of Calcineurin-dependent Pathway. Journal of Molecular and Cellular Cardiology (2001) 33, 249–259. Cardiac-specific expression of an activated calcineurin protein in the hearts of transgenic (CLN) mice produces a profound hypertrophy that rapidly progresses to heart failure. While calcineurin is regulated by Ca 2+ , the potential effects of calcineurin on cardiac myocyte Ca 2+ handling has not been evaluated. To this end, we examined L-type Ca 2+ currents (I Ca ) in left ventricular myocytes. CLN myocytes had larger (≈80%) cell capacitance and enhanced I Ca density (≈20%) compared with non-transgenic (NTG) littermates, but no change in the current–voltage relationship, single-channel conductance or protein levels of 1 or 2 subunit of L-type Ca 2+ channels. Interestingly, the kinetics of I Ca inactivation was faster (≈two-fold) in CLN myocytes compared with NTG myocytes. Ryanodine application slowed the rate of I Ca inactivation in both groups and abolished the kinetic difference, suggesting that Ca 2+ -dependent inactivation is increased in CLN myocytes due to altered SR Ca 2+ release. Treatment of CLN mice with Cyclosporine A (CsA), a calcineurin inhibitor, prevented myocyte hypertrophy and changes in I Ca activity and inactivation kinetics. However, there was no direct effect of CsA on I Ca in either NTG or CLN myocytes, suggesting that endogenous calcineurin activity does not directly regulate Ca 2+ channel activity. This interpretation is consistent with the observation that I Ca density, inactivation kinetics and regulation by isoproterenol were normal in cardiac-specific transgenic mice expressing calcineurin inhibitory protein domains from either Cain or AKAP79. Taken together these data suggest that chronic activation of calcineurin is associated with myocyte hypertrophy and a secondary enhancement of intracellular Ca 2+ handling that is tied to the hypertrophy response itself. 2001 Academic Press K W: Calcineurin; Cardiac hypertrophy; Calcium; Cyclosporine; Cain; AKAP79. ventricular dilation and congestive heart failure, Introduction which is associated with a markedly shortened life expectancy. 1 The identity of intracellular signaling Myocardial hypertrophy is an adaptive response to a variety of conditions that increase cardiac work. factors that trigger cardiac hypertrophy and reg- ulate the transition to heart failure remains an area The resulting increase in cardiac mass initially reduces wall stress and maintains ventricular func- of intense ongoing investigation. Cardiac hypertrophy is thought to be mediated tion. However, sustained hypertrophy can lead to Please address all correspondence to: Dr Atsuko Yatani, Cardiovascular Research Institute, UMDNJ-New Jersey Medical School, Hackensack University Medical Center, Hackensack, NJ 07601, USA. 0022–2828/01/020249+11 $35.00/0 2001 Academic Press