Distinct roles of CaM and Ca(2+)/CaM -dependent protein kinase II in Ca(2+) -dependent facilitation and inactivation of cardiac L-type Ca(2+) channels

Hong-Guang Nie, Li-Ying Hao, Jian-Jun Xu, Etsuko Minobe, Asako Kameyama, Masaki Kameyama
Journal of Physiological Sciences: JPS 2007, 57 (3): 167-73
L-type Ca(2+) channels have two opposing forms of autoregulatory feedback, Ca(2+) -dependent facilitation (CDF) and Ca(2+) -dependent inactivation (CDI), in response to increases in intracellular Ca(2+) concentration. Calmodulin (CaM) has been reported to mediate the two feedbacks. Although both the direct binding of CaM and the phosphorylation mediated by Ca(2+)/CaM -dependent protein kinase II (CaMKII) have been suggested as underlying mechanisms, the detailed features remain to be clarified. In this study, we investigated the effects of CaM and CaMKII inhibitors on CDF and CDI with patch clamp cell-attached recordings in guinea-pig ventricular myocytes. We confirmed that a high-K(+) and high-Ca(2)(+) could induce an increase of the intracellular Ca(2+) concentration and subsequent CDF and CDI. We then found that CDF and CDI were both depressed and were finally abolished by treatment with a CaM inhibitor chlorpromazine (1-100 microM) in a concentration-dependent manner. Another CaM antagonist calmidazolium (1 microM) showed a similar effect. In contrast, CaMKII inhibitors, KN-62 (0.1-3 microM) and autocamtide 2 -related inhibitory peptide (1 microM), delayed the development of CDF and CDI significantly, but they did not depress either CDF or CDI. These results imply that CaM is necessary and possibly sufficient for the two mechanisms. We propose a hypothesis that CaM is a key molecule to bifurcate the Ca(2+) signal to CDF and CDI and that CaMKII plays a modulatory role in them both.

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