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MEMBRANE TRANSPORTERS, ION CHANNELS, AND PUMPS

Calmodulin reverses rundown of L-type Ca²⁺ channels in guinea pig ventricular myocytes

Department of Physiology, Graduate School of Medical and Dental Sciences, Kagoshima University, Kagoshima 890-8544, Japan

Submitted 23 February 2004 ; accepted in final form 7 August 2004

Calmodulin (CaM) is implicated in regulation of Ca²⁺ channels as a Ca²⁺ sensor. The effect of CaM on rundown of L-type Ca²⁺ channels in inside-out patch form was investigated in guinea pig ventricular myocytes. Ca²⁺ channel activity disappeared within 1–3 min and did not reappear when the patch was excised and exposed to an artificial intracellular solution. However, application of CaM (0.03, 0.3, 3 µM) + 3 mM ATP to the intracellular solution within 1 min after patch excision resulted in dose-dependent activation of channel activity. Channel activity averaged 11.2%, 94.7%, and 292.9%, respectively, of that in cell-attached mode. Channel activity in inside-out patch mode was induced by CaM + ATP at nanomolar Ca²⁺ concentrations ([Ca²⁺]); however, increase to micromolar [Ca²⁺] rapidly inactivated the channel activity induced, revealing that the effect of CaM on the channel was Ca²⁺ dependent. At the 2nd, 4th, 6th, 8th, and 10th minutes after patch excision, CaM (0.75 µM) + ATP induced Ca²⁺ channel activity to 150%, 100%, 96.9%, 29.3%, and 16.6%, respectively, revealing a time-dependent action of CaM on the channel. CaM added with adenosine 5'-(,-imido)triphosphate (AMP-PNP) also induced channel activity, although with much lower potency and shorter duration. Protein kinase inhibitors KN-62, CaM-dependent protein kinase (CaMK)II 281-309, autocamtide-related CaMKII inhibitor peptide, and K252a (each 1–10 µM) did not block the effect of CaM, indicating that the effect of CaM on the Ca²⁺ channel was phosphorylation independent. Neither CaM nor ATP alone induced Ca²⁺ channel activity, showing a cooperative effect of CaM and ATP on the Ca²⁺ channel. These results suggest that CaM is a crucial regulatory factor of Ca²⁺ channel basal activity.

cardiac myocyte; calcium channel; patch clamp

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