Afterhyperpolarization regulates firing rate in neurons of the suprachiasmatic nucleus.

Cluster I neurons of the suprachiasmatic nucleus (SCN), which are thought to be pacemakers supporting circadian activity, fire spontaneous action potentials that are followed by a monophasic afterhyperpolarization (AHP). Using a brain slice preparation, we have found that the AHP has a shorter duration in cells firing at higher frequency, consistent with circadian modulation of the AHP. The AHP is supported by at least three subtypes of K(Ca) channels, including apamin-sensitive channels, iberiotoxin-sensitive channels, and channels that are insensitive to both of these antagonists. The latter K(Ca) channel subtype is involved in rate-dependent regulation of the AHP. Voltage-clamped, whole-cell Ca(2+) channel currents recorded from SCN neurons were dissected pharmacologically, revealing all of the major high-voltage activated subtypes: L-, N-, P/Q-, and R-type Ca(2+) channel currents. Application of Ca(2+) channel antagonists to spontaneously firing neurons indicated that predominantly L- and R-type currents trigger the AHP. Our findings suggest that apamin- and iberiotoxin-insensitive K(Ca) channels are subject to diurnal modulation by the circadian clock and that this modulation either directly or indirectly leads to the expression of a circadian rhythm in spiking frequency.

Modulation of single channels underlying hippocampal L-type current enhancement by agonists depends on the permeant ion.

The influx of calcium (Ca(2+)) ions through L-type channels underlies many cellular processes, ranging from initiation of gene transcription to activation of Ca(2+)-activated potassium channels. L-type channels possess a diagnostic pharmacology, being enhanced by the dihydropyridine BAY K 8644 and benzoylpyrrole FPL 64176. It is assumed that the action of these compounds is independent of the ion conducted through the channel. In contrast to this assumption, modulation of L-type channel activity in acutely dissociated rat CA1 hippocampal neurons depended on the divalent ion identity. BAY K 8644 and FPL 64176 substantially increased single-channel open time only when barium (Ba(2+)) was the permeant ion. BAY K 8644 increased single-channel conductance when either Ba(2+) or Ca(2+) ions were the charge carrier, an effect not observed with FPL 64176. BAY K 8644 enhanced the whole cell L-type channel Ca(2+)- or Ba(2+)-carried current without a change in deactivation tail kinetics. In contrast, enhancement by FPL 64176 was associated with a dramatic slowing of deactivation kinetics only when Ba(2+) and not Ca(2+) was the charge carrier. Current activation was slowed by FPL 64176 with either charge carrier, an effect arising from a clustering of agonist-modified long-duration openings toward the end of the voltage step. These data indicate that agonists enhanced L-type current by distinct mechanisms dependent on the permeant ion, indicating that care must be considered when used as diagnostic tools.