Elevation of intracellular Ca2+ modulates A-currents in rat cerebellar granule neurons

In the brain, the transient-inactivating voltage-gated potassium channel currents (called I(K(A)) or A-currents) are activated at subthreshold membrane potentials to control the excitability of neurons. In the current study, the effect of intracellular calcium on the A-current and the action mechanism of intracellular calcium was investigated by using the whole-cell voltage-clamp technique. Elevation of intracellular calcium by addition of 2 mM CaCl2 in the pipette solution significantly modulated both the peak amplitude and the kinetics of the A-current in rat granule neurons. The peak amplitudes of the A-current were 1,060 +/- 87 pA and 1,972 +/- 16 pA under conditions of no Ca2+ and elevated intracellular Ca2+, respectively. The time to peak, the time course of fast inactivation, and the steady-state inactivation property of the A-current were all significantly altered by elevating the intracellular Ca2+. Replacement of the Ca2+ in the pipette solution with the same concentration of Co2+ did not mimic the effects of intracellular Ca2+ on the A-current amplitude and kinetics. These effects are similar to the behavior of the reconstituted Kv4/KChIP (K(V) channel-interacting proteins) current induced by expression of KChIP and Kv4 together in a cell expression system. Application of 10 microM arachidonic acid, which can bind to the Kv4/KChIP complex, inhibited the A-current and eliminated the effects of intracellular Ca2+ on the A-current, suggesting that KChIP may be involved in the effects of Ca2+ on the A-current. Collectively, our results indicate that elevated intracellular Ca2+ modulates the amplitude, fast activation, and steady-state inactivation characteristics of the A-current in rat cerebellar granule neurons, and this may occur via KChIP.