Key result
CaMKII interaction with the COOH terminus of the pore-forming subunit alpha1C is essential for Ca2+-dependent facilitation of L-type calcium channels.
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Hypothesis-generating for CaMKII modulation of L-type currents; leaves open in vivo relevance and clinical translation.
Ca2+-dependent facilitation (CDF) of voltage-gated calcium current is a powerful mechanism for up-regulation of Ca2+ influx during repeated membrane depolarization. CDF of L-type Ca2+ channels (Ca(v)1.2) contributes to the positive force-frequency effect in the heart and is believed to involve the activation of Ca2+/calmodulin-dependent kinase II (CaMKII). How CaMKII is activated and what its substrates are have not yet been determined. We show that the pore-forming subunit alpha(1C) (Ca(v)alpha1.2) is a CaMKII substrate and that CaMKII interaction with the COOH terminus of alpha1C is essential for CDF of L-type channels. Ca2+ influx triggers distinct features of CaMKII targeting and activity. After Ca2+-induced targeting to alpha1C, CaMKII becomes tightly tethered to the channel, even after calcium returns to normal levels. In contrast, activity of the tethered CaMKII remains fully Ca2+/CaM dependent, explaining its ability to operate as a calcium spike frequency detector. These findings clarify the molecular basis of CDF and demonstrate a novel enzymatic mechanism by which ion channel gating can be modulated by activity.
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Hudmon et al. (2005) studied this question. CaMKII interaction with the COOH terminus of the pore-forming subunit alpha1C is essential for Ca2+-dependent facilitation of L-type calcium channels.
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