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Intracellular Ca²⁺ regulates responsiveness of cardiac L-type Ca²⁺ current to protein kinase A: role of calmodulin

Department of Pharmacology, Physiology, and Neuroscience, School of Medicine, University of South Carolina, Columbia, South Carolina 29208

Submitted 26 March 2003 ; accepted in final form 8 September 2003

The goal of this study was to determine whether the protein kinase A (PKA) responsiveness of the cardiac L-type Ca²⁺ current (I_Ca) is affected during transient increases in intracellular Ca²⁺ concentration. Ventricular myocytes were isolated from 3- to 4-day-old neonatal rats and cultured on aligned collagen thin gels. When measured in 1 or 2 mM Ca²⁺ external solution, the aligned myocytes displayed a large I_Ca that was weakly regulated (20% increase) during stimulation of PKA by 2 µM forskolin. In contrast, application of forskolin caused a 100% increase in I_Ca when the external Ca²⁺ concentration was reduced to 0.5 mM or replaced with Ba²⁺. This Ca²⁺-dependent inhibition was also observed when the cells were treated with 1 µM isoproterenol, 100 µM 3-isobutyl-1-methylxanthine, or 500 µM 8-bromo-cAMP. The responsiveness of I_Ca to PKA was restored during intracellular dialysis with a calmodulin (CaM) inhibitory peptide but not during treatment with inhibitors of protein kinase C, Ca²⁺/CaM-dependent protein kinase, or calcineurin. Adenoviral-mediated expression of a CaM molecule with mutations in all four Ca²⁺-binding sites also increased the PKA sensitivity of I_Ca. Finally, adult mouse ventricular myocytes displayed a greater response to forskolin and cAMP in external Ba²⁺. Thus Ca²⁺ entering the myocyte through the voltage-gated Ca²⁺ channel regulates the PKA responsiveness of I_Ca.

heart; calcium channels; -adrenergic; cAMP