The gating kinetics of the slow vacuolar channel. A novel mechanism for SV channel functioning?

Abstract

Although there is consensus that the slow vacuolar or SV channel is a Ca2+ release channel, the underlying mechanism of operation is still controversial. The main reason is that the voltage sensitivity of SV gating seems to exclude activation at hyperpolarized (physiological) membrane potentials. Inspired by a study of Gambale et al. (1993) and supported by simulation studies presented here, we interpreted SV activation and deactivation kinetics in terms of a cyclic state diagram originally applied to animal cation-selective channels. A cyclic state diagram allows two pathways of activation operating in opposite directions. One pathway represents the frequently observed slow activation at moderate depolarization (< 130 mV). With the open state (O) next to the closed state initially occupied (C-1), direct transitions from C-1 to O can account for the fast activation observed at higher depolarized potentials (>130 mV). We hypothesize that similar state transitions directly to O may also occur during hyperpolarization. The implication of this proposed mechanism is that SV accomplishes its physiological role during hyperpolarization-evoked deactivation. Despite their rare occurrence and possibly short duration, these opening events may last long enough to substantially raise the local cytosolic free Ca2+ level at the channel mouth by as much as 600 nM/ms. Because under in vivo conditions the Ca2+ flux is inwardly directed, the mechanism presented here revives the notion that the SV channel can be subject to calcium-induced calcium release.