Long-opening mode of gating of neuronal calcium channels and its promotion by the dihydropyridine calcium agonist Bay K 8644.

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Abstract
A large-conductance Ca channel in chicken dorsal root ganglion neurons was studied with patch-clamp recordings of unitary currents. In addition to the conventional pattern of Ca-channel gating previously described in neurons (mode 1), a different form of gating behavior (mode 2) was observed. Unlike the brief (.simeq. 1 ms) openings in mode 1, mode 2 openings tend to be longer (> 10 ms) and often outlast the test pulse. In mode 2, the probability of channel openness (P) is high at relatively negative potentials where P in mode 1 is low. Mode 2 activity appears much less often than mode 1 activity in the absence of drug. The balance is strongly shifted in favor of mode 2 by the dihydropyridine Ca agonist Bay K 8644 [methyl-1,4-dihydro-2,6-dimethyl-3-nitro-4-(2-trifluoromethylphenyl)pyridine-5-carboxylate], an effect that underlies a marked enhancement of Ca-channel activity. This is the first evidence for dihydropyridine control of neuronal Ca-channel function at the single-channel level. Sweeps showing mode 1 or mode 2 gating appeared interspersed with sweeps with no openings, during which the channel was unavailable for opening (null mode or mode 0). Two approaches showed that switching between all 3 modes occurred on a time scale of seconds: channels tended to remain in the same mode from one sweep to the next, with pulses at 0.25 Hz; and steady depolarizations in Bay K8644 produced clusters of mode 2 openings lasting several seconds. Changes in the rates of switching might be important in neurochemical modulation of Ca channels. Bay K 8644 and other dihydropyridine Ca agonists might be useful experimental tools for manipulating transmitter release, neurite extension and other neuronal functions dependent on intracellular Ca.