A study of the mechanism of Ca2+ current inhibition produced by serotonin in rat dorsal raphe neurons

Abstract

Calcium currents and their modulation by 5-HT were studied using both whole-cell and single-channel patch-clamp techniques in acutely isolated adult rat dorsal raphe neurons. Evidence for three types of Ca channels (T, N, L) was obtained in both whole-cell and single-channel experiments. Approximately 4% of the total high-threshold Ca current (L-type) was sensitive to dihydropyridines (DHPs) while approximately 40% of the Ca current (N-type) was sensitive to omega-conotoxin (omega-CgTx). About 56% of the whole-cell current was insensitive to either DHPs or omega-CgTx and may thus represent a different kind of Ca current. 5-HT reduced raphe neuron Ca currents by approximately 50%, while slowing activation. 5-HT inhibited both omega-CgTx-sensitive and -insensitive Ca current. Inhibition by 5-HT was voltage dependent; prepulses to +80 mV lasting for 20 msec almost completely abolished the 5-HT-mediated inhibition. The voltage dependence of the response to 5-HT suggested that trains of action potentials might overcome the inhibition due to 5-HT. Trains of brief depolarizations were used to simulate action potentials; only about 5% of the 5-HT-induced inhibition was relieved by the trains. These results suggest that while large depolarizations could restore the Ca current inhibited by 5-HT, physiological stimuli, such as trains of action potentials, could not. The action of 5-HT was made irreversible by inclusion of GTP-gamma-S in the patch pipette, suggesting a G-protein mediation of the response to 5-HT.(ABSTRACT TRUNCATED AT 250 WORDS)

Serotonergic Inhibition of the T-Type and High Voltage-Activated Ca2+Currents in the Primary Sensory Neurons ofXenopusLarvae

“…Squares, Control; filled circles, 5-HT (1 M). (Bayliss, 1995), or N-type currents in sensory neurons (Del Mar et al, 1994) and other C NS neurons (Pennington et al, 1991;Koike et al, 1994). Consistent with these reports, our results showed that N-and P/Q-type H VA C a 2ϩ current was inhibited by 5-HT in R-B neurons.…”

“…The 5-HT 1A receptor can inhibit Ca 2ϩ entry through HVA channels into afferent terminals of nociceptors in mammalian spinal cord (Del Mar et al, 1994). 5-HT 1A receptors also have been reported to be involved in the voltage-dependent G-protein-coupled inhibition of the HVA currents in other CNS neurons (Pennington et al, 1991;Koike et al, 1994;Bayliss et al, 1995;Foehring, 1996). Unlike these previous reports, the inhibition of the HVA currents by 5-HT 1A receptors in Xenopus R-B neurons is not voltage-dependent.…”

“…One possible action is to inhibit Ca 2ϩ entry into sensory neurons (Del Mar et al, 1994). In other CNS neurons N-type or P/Q-type high voltage-activated (HVA) calcium channels can be modulated by serotonin, mostly via 5-HT 1A receptor and membrane-delimited G-protein pathways (Pennington et al, 1991;Koike et al, 1994;Bayliss et al, 1995;Foehring et al, 1996). These calcium channels are known to be involved in triggering synaptic transmission (Luebke et al, 1993;Luebke and Dunlap, 1994;Wall and Dale, 1994;Wheeler et al, 1994) (for review, see Dunlap, 1997).…”

Comparison of N- and P/Q-Type Voltage-Gated Calcium Channel Current Inhibition

“…There is general consensus that this involves a direct effect of the activated G-protein subunit or subunits on the calcium channel itself, and recent evidence indicates a key role for the G-protein ␤␥ subunits (Herlitze et al, 1996;Ikeda, 1996). The inhibition exhibits characteristic gating shifts manifested as slowed activation kinetics, a diminution of the inhibition at positive membrane potentials, and partial relief from inhibition by conditioning prepulses (Bean, 1989;Elmslie et al, 1990;Penington et al, 1991). These effects have been incorporated into models in which the channels exhibit two functional gating states, one in the presence ("reluctant") and another in the absence ("willing") of inhibition (Bean, 1989;Elmslie et al, 1990;Boland and Bean, 1993;Golard and Siegelbaum, 1993).…”

“…This would be achieved if there were relief from inhibition during trains of action potentials. However, use of short depolarizing steps to mimic action potentials suggests that for N-type channels this may be confined to cells capable of firing at very high rates (Penington et al, 1991;Williams et al, 1997). Relief of P/Q-type channel inhibition by action potentials may depend on the duration of the action potential waveform (Brody et al, 1997).…”