Modulation of calcium currents by electrical activity

1. Electrical activation of mouse dorsal root ganglion (DRG) neurons in cultures for 1-2 days produced a downregulation of voltage-sensitive calcium currents, which persisted for greater than or equal to 24 h after stimulation was terminated. This regulation varied with different patterns of activation. Both the magnitude and time course of regulation of the low-threshold voltage-activated (LVA) and high-threshold voltage-activated (HVA) currents were differentially sensitive to neural impulse activity. Tonic stimulation at 0.5 Hz did not affect the HVA currents, but 2.5 Hz did produce a significant decrease. Phasic stimulation (10 Hz for 0.5 s every 2 s) with an average frequency of 2.5 Hz produced significantly more downregulation of HVA currents than did the tonic 2.5-Hz stimulation. The efficacy of phasic stimulation varied inversely with the interval between bursts. Thus phasic stimulation of 10 Hz for 0.5 s but delivered every 4 s produced no effects on HVA currents. Stimulation optimal for downregulation of Ca2+ currents also produced a decreased binding by the DRG neurons of an L-type Ca2+ channel antagonist. This suggests a downregulation by electrical activity of the number of Ca2+ channels, rather than an alteration in a constant number of channels. Depression of LVA currents was produced by all stimulus patterns tested, including 0.5-Hz tonic stimulation. Chronic stimulation with a stimulation pattern that downregulated Ca2+ currents also produced a slowing of the increase in intracellular Ca2+ (as measured by Fura-2/AM) that is produced acutely by repetitive stimulation. This is consonant with earlier studies of intracellular Ca2+ concentration kinetics in growth cones.