Autoreceptors, membrane potential and the regulation of transmitter release

It has been suggested that depolarization per se can control neurotransmitter release, in addition to its role in promoting Ca²⁺ influx. The 'Ca²⁺ hypothesis' has provided an essential framework for understanding how Ca²⁺ entry and accumulation in nerve terminals controls transmitter release. Yet, increases in intracellular Ca²⁺ levels alone cannot account for the initiation and termination of release; some additional mechanism is needed. Several experiments from various laboratories indicate that membrane potential has a decisive role in controlling this release. For example, depolarization causes release when Ca²⁺ entry is blocked and intracellular Ca²⁺ levels are held at an elevated level. The key molecules that link membrane potential with release control have not yet been identified: likely candidates are presynaptic autoreceptors and perhaps the Ca²⁺ channel itself.