Calcium is essential but insufficient for neurotransmitter release: the calcium-voltage hypothesis

A new Ca-voltage hypothesis for neurotransmitter release is proposed. Accordingly, membrane depolarization has two roles. To increase membrane conductance to calcium and to activate a molecule S from an inactive form T. Only the active form S binds calcium ions to start the chain of events leading to release. Four lines of experiments are described to support this hypothesis. Disassociation between Ca2+ entry and transmitter release. Loading of the terminal with Ca2+ and obtaining release with little additional entry of Ca2+. Measurements of kinetics of release. Modulation of release by changes in membrane potential. Recent criticism as to the validity of the experimental techniques used in the first two lines of experiments is analyzed and rejected.