3 years ago

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

Clive H Orchard, Mark B Cannell, Andrew F James, Simon M Bryant, Cherrie H T Kong
β2-adrenoceptors and the L-type Ca current (ICa) 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 (Cav-3) and protein kinase A (PKA) signaling, both of which have previously been implicated in this redistribution. ICa 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 weeks earlier. ICa distribution between the surface and t-tubule membranes was determined using formamide-induced detubulation (DT). In Sham myocytes, β2-adrenoceptor stimulation increased ICa in intact, but not DT myocytes; however, forskolin (to increase cAMP directly) and H-89 (to inhibit PKA) increased and decreased, respectively, ICa at both the surface and t-tubule membranes. C3SD peptide (which decreases binding to Cav-3) inhibited ICa in intact but not DT myocytes, but had no effect in the presence of H-89. In contrast, in CAL myocytes, β2-adrenoceptor stimulation increased ICa in both intact and DT myocytes, but C3SD had no effect on ICa; forskolin and H-89 had similar effects as in Sham myocytes. These data show redistribution of β2-adrenoceptor activity and ICa in CAL myocytes, and suggest constitutive stimulation of ICa by PKA in Sham myocytes via concurrent Cav-3-dependent (at the t-tubules) and Cav-3-independent mechanisms, with the former being lost in CAL myocytes.

Publisher URL: http://doi.org/10.1152/ajpheart.00458.2017

DOI: 10.1152/ajpheart.00458.2017

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