Enhanced Ca2+ channel currents in cardiac hypertrophy induced by activation of calcineurin-dependent pathway

Cardiac-specific expression of an activated calcineurin-protein in the hear ts of transgenic (CLN) mice produces a profound hypertrophy that rapidly pr ogresses to hart Failure. While calcineurin is regulated by Ca2+, the poten tial effects of calcineurin on cardiac myocyte Ca2+ handling has not been e valuated. To this end, we examined L-type Ca2+ currents (I-Ca) in left vent ricular myocytes. CLN myocytes had larger (approximate to 80%) cell capacit ance and enhanced I-Ca density (approximate to 20%) compared with non-trans genic (NTG) littermates, but no change in the current-voltage relationship, single-channel conductance or protein levels of alpha1 or beta2 subunit of L-type Ca2+ channels. Interestingly, the kinetics of I-Ca inactivation was faster (approximate to two-fold) in CLN myocytes compared with NTG myocyte s. Ryanodine application slowed the rate of I-Ca inactivation in both group s and abolished the kinetic difference, suggesting that Ca2+-dependent inac tivation is increased in CLN myocytes due to altered SR Ca2+ release. Treat ment of CLN mice with Cyclosporine A (CsA), a calcineurin inhibitor, preven ted myocyte hypertrophy and changes in I-Ca activity and inactivation kinet ics. However, there was no direct effect of CsA on I-Ca in either NTG or CL N myocytes, suggesting that endogenous calcineurin activity does not direct ly regulate Ca2+ channel activity. This interpretation is consistent with t he observation that I-Ca density, inactivation kinetics and regulation by i soproterenol were normal in cardiac-specific transgenic mice expressing cal cineurin inhibitory protein domains from either Cain or AKAP79. Taken toget her these data suggest that chronic activation of calcineurin is associated with myocyte hypertrophy and a secondary enhancement of intracellular Ca2 handling that is tied to the hypertrophy response itself. (C) 2001 Academi c Press.