Loss of caveolin-3-dependent regulation of I(Ca) in rat ventricular myocytes in heart failure

β(2)-Adrenoceptors and L-type Ca(2+) current (I(Ca)) redistribute from the t-tubules to the surface membrane of ventricular myocytes from failing hearts. The present study investigated the role of changes in caveolin-3 and PKA signaling, both of which have previously been implicated in this redistribution. I(Ca) was recorded using the whole cell patch-clamp technique from ventricular myocytes isolated from the hearts of rats that had undergone either coronary artery ligation (CAL) or equivalent sham operation 18 wk earlier. I(Ca) distribution between the surface and t-tubule membranes was determined using formamide-induced detubulation (DT). In sham myocytes, β(2)-adrenoceptor stimulation increased I(Ca) in intact but not DT myocytes; however, forskolin (to increase cAMP directly) and H-89 (to inhibit PKA) increased and decreased, respectively, I(Ca) at both the surface and t-tubule membranes. C3SD peptide (which decreases binding to caveolin-3) inhibited I(Ca) in intact but not DT myocytes but had no effect in the presence of H-89. In contrast, in CAL myocytes, β(2)-adrenoceptor stimulation increased I(Ca) in both intact and DT myocytes, but C3SD had no effect on I(Ca); forskolin and H-89 had similar effects as in sham myocytes. These data show the redistribution of β(2)-adrenoceptor activity and I(Ca) in CAL myocytes and suggest constitutive stimulation of I(Ca) by PKA in sham myocytes via concurrent caveolin-3-dependent (at the t-tubules) and caveolin-3-independent mechanisms, with the former being lost in CAL myocytes. NEW & NOTEWORTHY In ventricular myocytes from normal hearts, regulation of the L-type Ca(2+) current by β(2)-adrenoceptors and the constitutive regulation by caveolin-3 is localized to the t-tubules. In heart failure, the regulation of L-type Ca(2+) current by β(2)-adrenoceptors is redistributed to the surface membrane, and the constitutive regulation by caveolin-3 is lost.