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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 &amp; 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.

Loss of caveolin-3-dependent regulation ofICain rat ventricular myocytes in heart failure

Loss of caveolin-3-dependent regulation ofI_Cain rat ventricular myocytes in heart failure