Ca
2+ dependent and Ca
2+ independent regulation mechanisms of neurotransmitter release at the synapse were reviewed. A Ca
2+ -chelator, BAPTA, was loaded into the presynapic nerve terminal of the frog neuromuscular junction. Then, among four components of nerve-stimulation induced increases in transmitter release, the fast facilitation was completely eliminated, while the other three slower components: the slow facilitation, augmentation and potentiation, remained unaffected, The fast facilitation was recovered, when the external Ca
2+ was introduced into the nerve terminal. This is a strong support for the residual Ca
2+ hypothesis on the fast facilitation and shows that the three slower components occur independently of internal Ca
2+ concentration. ATP, TNBS, crotoxin, erithrosin B and hypertonicity were also suggested to modulate the release independently of internal Ca
2+ concentration. Ca
2+ independent regulation of transmitter release has also been reported on many other synapses, recently.
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