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alpha1-Adrenoceptor stimulation (alpha1ARS) modulates cardiac muscle contraction under physiological conditions by means of changes in Ca2+ current through L-type channels (ICa,L) and Ca2+ sensitivity of the myofilaments. However, the cellular mechanisms of alpha1ARS are not fully clarified. In this study, we investigated the role of Ca2+/calmodulin-dependent PK II (CaMKII) in the regulation of ICa,L during alpha1ARS in isolated adult rat ventricular myocytes by using the perforated patch-clamp technique. CaMKII inhibition with 0.5 microM KN-93 abolished the potentiation in ICa,L observed during alpha1ARS by 10 microM phenylephrine. In the presence of PKC inhibitor (10 microM chelerythrine), the potentiation of ICa,L by phenylephrine also disappeared. In Western immunoblotting analysis, phenylephrine (&gt; or =1 microM) increased the amount of autophosphorylated CaMKII (active CaMKII) significantly, and this increase was abolished by CaMKII inhibition or PKC inhibition. Also, we investigated changes in the subcellular localization of active CaMKII by using immunofluorescence microscopy and immunoelectron microscopy. Before alpha1ARS, active CaMKII was exclusively located just beneath the plasmalemma. However, after alpha1ARS, active CaMKII was localized close to transverse tubules, where most of L-type Ca2+ channels are located. From these results, we propose that CaMKII, which exists near transverse tubules, is activated and phosphorylated by alpha1ARS and that CaMKII activation directly potentiates ICa,L in rat ventricular myocytes.

proceedings of the national academy of sciences of the united states of america

α 1 -Adrenoceptor stimulation potentiates L-type Ca 2+ current through Ca 2+ /calmodulin-dependent PK II (CaMKII) activation in rat ventricular myocytes