Long-Opening Mode of Gating of Neuronal Calcium Channels and Its Promotion by the Dihydropyridine Calcium Agonist Bay K 8644

A large-conductance calcium 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''), we observed a different form of gating behavior (``mode 2''). Unlike the brief (≈ 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. However, the balance is strongly shifted in favor of mode 2 by the dihydropyridine Ca agonist Bay K 8644, 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 three modes occurred on a time scale of seconds: (i) channels tended to remain in the same mode from one sweep to the next, with pulses at 0.25 Hz; and (ii) steady depolarizations in Bay K 8644 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.