Synaptotagmin Regulation of Secretory Mode

Abstract

Vesicular secretion of neurotransmitter can take place through two distinct mechanisms: full fusion, in which a fusion pore opens and dilates and the vesicle completely releases its contents; and kiss-and-run, in which the fusion pore opens but does not dilate. Wang et al. performed amperometric measurements of catecholamine release in cultured pheochromocytoma 12 (PC12) cells to distinguish between these two forms of secretion and to investigate the role of synaptotagmins (Syts) in regulating the choice of secretory mode. Syts are a family of synaptic vesicle proteins that contain two calcium-binding C 2 domains (C 2 A and C 2 B). Full fusion events led to brief "spikes" of high concentrations of released catecholamine, whereas kiss-and-run events led to more prolonged release of low concentrations of transmitter. Overexpression or pharmacological manipulations that increased Syt IV--the expression of which is increased by seizures--led to increased frequency and duration of kiss-and-run episodes. Mutational analysis of transfected Syt I and Syt IV, in combination with analysis of the calcium dependence of secretion in permeabilized cells, indicated that Syt I promoted full fusion (through its C 2 A domain) whereas Syt IV promoted kiss-and-run secretion (through its C 2 B domain). The authors speculate that prolonged release of low levels of neurotransmitter in response to increased synaptic Syt IV concentrations could desensitize postsynaptic receptors, thereby silencing the synapse and serving as a homeostatic mechanism to counteract seizure activity. C.-T. Wang, J.-C. Lu, J. Bai, P. Y. Chang, T. F. J. Martin, E. R. Chapman, M. B. Jackson, Different domains of synaptotagmin control the choice between kiss-and-run and full fusion. Nature 424 , 943-947 (2003). [Online Journal]