Acta Pharmacologica Sinica 2007 December; 28 (12): 1891-1897; doi: 10.1111/j.1745-7254.2007.00730.x

Aim: The aim of the present study was to investigate the electrophysiological actions of cyclosporin A (CsA) and tacrolimus (FK506) on neurons in the brain, and to elucidate the relevant mechanisms.

Methods: Whole-cell current-clamp recording was made in CA1 pyramidal neurons in rat hippocampal slices; whole-cell voltage-clamp recording was made in dissociated hippocampal CA1 pyramidal neurons of rats.

Results: CsA (100 µmol/L) and FK506 (50 µmol/L) did not significantly alter the passive electrical properties of hippocampal CA1 pyramidal neurons, but slowed down the repolarizing phase of the action potential. CsA (10_100 µmol/L) selectively inhibited the delayed rectifier K⁺ current (I_K) in a concentration-dependent manner. CsA did not affect the kinetic properties of I_K. Intracellular dialysis of CsA (100 µmol/L) had no effect on I_K. The inhibition of I_K by CsA (100 µmol/L) persisted under the low Ca²⁺ conditions that blocked the basal activity of calcineurin.

Conclusion: CsA exerted calcineurin-independent inhibition on the I_K in rat hippocampal pyramidal neurons. Taken together with our previous finding with FK506, it is conceivable that the spike broadening caused by the immunosuppressant drugs is due to direct inhibition on the I_K.

Keywords: action potential; calcineurin; cyclosporin A; delayed rectifier K⁺ channel; hippocampus; tacrolimus