Can the Ca2+ hypothesis and the Ca2+-voltage hypothesis for neurotransmitter release be reconciled?

It is well established that Ca2+ plays a key role in promoting the physiological depolarization-induced release (DIR) of neurotransmitters from nerve terminals (Ca2+ hypothesis). Yet, evidence has accumulated for the Ca2+-voltage hypothesis, which states that not only is Ca2+ required, but membrane potential as such also plays a pivotal role in promoting DIR. An essential aspect of the Ca2+-voltage hypothesis is that it is depolarization that is responsible for the initiation of release. This assertion seems to be contradicted by recent experiments wherein release was triggered by high concentrations of intracellular Ca2+ in the absence of depolarization [calcium-induced release (CIR)]. Here we show that there is no contradiction between CIR and the Ca2+-voltage hypothesis. Rather, CIR can be looked at as a manifestation of spontaneous release under conditions of high intracellular Ca2+ concentration. Spontaneous release in turn is governed by a subset of the molecular scheme for DIR, under conditions of no depolarization. Prevailing estimates for the intracellular calcium concentration, [Ca2+]i, in physiological DIR rely on experiments under conditions of CIR. Our theory suggests that these estimates are too high, because depolarization is absent in these experiments and [Ca2+]i is held at high levels for an extended period.