An R-type Ca2+ current in neurohypophysial terminals preferentially regulates oxytocin secretion

Abstract

Multiple types of voltage-dependent Ca2+ channels are involved in the regulation of neurotransmitter release (Tsien et al., 1991; Dunlap et al., 1995). In the nerve terminals of the neurohypophysis, the roles of L-, N-, and P/Q-type Ca2+ channels in neuropeptide release have been identified previously (Wang et al., 1997a). Although the L- and N-type Ca2+ currents play equivalent roles in both vasopressin and oxytocin release, the P/Q-type Ca2+ current only regulates vasopressin release. An oxytocin-release and Ca2+ current component is resistant to the L-, N-, and P/Q-type Ca2+ channel blockers but is inhibited by Ni2+. A new polypeptide toxin, SNX- 482, which is a specific α(1E)-type Ca2- channel blocker (Newcomb et al., 1998), was used to characterize the biophysical properties of this resistant Ca2+ current component and its role in neuropeptide release. This resistant component was dose dependently inhibited by SNX-482, with an IC50 of 4.1 nM. Furthermore, SNX-482 did not affect the other Ca2+ current types in these CNS terminals. Like the N- and P/Q-type Ca2+ currents, this SNX-482- sensitive transient Ca2+ current is high-threshold activated and shows moderate steady-state inactivation. At the same concentrations, SNX-482 blocked the component of oxytocin, but not of vasopressin, release that was resistant to the other channel blockers, indicating a preferential role for this type of Ca2+ current in oxytocin release from neurohypophysial terminals. Our results suggest that an α(1E) or 'R'-type Ca2+ channel exists in oxytocinergic nerve terminals and, thus, functions in controlling only oxytocin release from the rat neurohypophysis.