Ca2+-dependent modulation of single human cardiac L-type calcium channels by the calcineurin inhibitor cyclosporine

Objective. – Activity of single L-type calcium channels (LTCC) is enhanced in human failing myocardium (Circulation 98 (1998) 969.), most likely due to impaired dephosphorylation. Protein phosphatase 2B (calcineurin) has recently been shown to be involved in heart failure pathophysiology. We now focus on the regulation of single LTCC by calcineurin that were prevented by Ca2+-free experimental conditions in our previous study. Methods. – Single LTCC currents were recorded in myocytes from human atrium and ventricle. Charge carriers were 70 mM Ba2+, or a mixture of 30 mM Ca2+ and 60 mM Ba2+ to facilitate Ca2+ permeation through recorded channels. The calcineurin inhibitor cyclosporine (10 μM) was used to reveal a putative role for calcineurin in regulation of LTCC. Results. – A mixture of Ca2+ and Ba2+ as charge carriers allowed for Ca2+ permeation through recombinant human embryonic kidney cells and native (atrial and ventricular) human cardiac LTCC. With only Ba2+ as the charge carrier, activities of both ventricular and atrial LTCC were strongly decreased by cyclosporine. In contrast, channel activity remained constant when Ca2+ permeation was provided. In the presence of thapsigargin and (S)-BayK 8644, cyclosporine here even increased channel activity. Conclusions. – We propose a dual cyclosporine effect on human cardiac LTCC. A non-specific inhibitory effect prevails with Ba2+ permeation but can be compensated or overcome by a specific Ca2+-dependent stimulation with Ca2+ permeation. More complete restoration of physiological Ca2+ movements (e.g., Ca2+ release from sarcoplasmic reticulum) will help to define even more precisely the involvement of calcineurin in regulation of human cardiac LTCC.