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Modulation of Ca²⁺-dependent Cl^- channels by calcineurin in rabbit coronary arterial myocytes

Jonathan Ledoux*, Iain Greenwood†, Louis R. Villeneuve* and Normand Leblanc‡

The role of the Ca²⁺-dependent phosphatase calcineurin (CaN) in the modulation of Ca²⁺-dependent Cl^- channels (Cl_Ca) was studied in freshly isolated rabbit coronary arterial myocytes. Immunocytochemical experiments showed that calmodulin-dependent protein kinase II (CaMKII) and CaN were distributed evenly throughout the cytoplasm of coronary myocytes at rest and translocated to the plasmalemma when intracellular Ca²⁺ was increased. Cl_Ca currents (I_Cl(Ca)) elicited by cell dialysis with fixed intracellular Ca²⁺ levels up to 500 nM were inhibited by 10 µM cyclosporin A (CsA), a specific inhibitor of CaN, in a voltage-dependent manner, whereas currents evoked by 1 µM Ca²⁺ were not affected. Inhibition of CaN with CsA also led to a significant reduction in Ca²⁺ sensitivity of the channel at +50 mV; half-maximal activation increased from 363 ± 16 nM Ca²⁺ in control to 515 ± 40 nM Ca²⁺ in the presence of CsA. Similar effects were observed on I_Cl(Ca) when a specific peptide fragment inhibitor of CaN (CaN-AF, 5 µM) was dialysed into the cell via the pipette (500 nM Ca²⁺). Application of KN-93 (10 µM), a specific inhibitor of CaMKII, enhanced I_Cl(Ca) in myocytes dialysed with 1 µM Ca²⁺ but produced no significant effect on this current when the cells were dialysed with 350 or 500 nM Ca²⁺. These results are consistent with the notion that in coronary arterial cells, the activity of Cl_Ca is enhanced by dephosphorylation of the channel or a closely associated regulatory protein. Moreover the balance of CaN and CaMKII regulating I_Cl(Ca) is dependent on the level of Ca²⁺ used to activate I_Cl(Ca).

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