Distinct fusion properties of synaptotagmin-1 and synaptotagmin-7 bearing dense core granules

Abstract

Adrenal chromaffin cells express two synaptotagmin isoforms, Syt-1 and Syt-7. Isoforms are usually sorted to separate secretory granules, are differentially activated by depolarizing stimuli, and favor discrete modes of exocytosis. It is proposed that stimulus/Ca+-dependent secretion in the chromaffin cell relies on selective Syt isoform activation.

Regulation of insulin exocytosis by calcium-dependent protein kinase C in beta cells

“…Synaptotagmin isoforms have different affinities for calcium, suggesting that they could mediate exocytosis of distinct vesicle pools in vivo [125]. Sorting of Syt-1 and Syt-7 onto distinct vesicle pools occurs in chromaffin cells and affects exocytotic behavior [127]. …”

“…For example, phosphorylation of synaptotagmin-7 by PKC would enhance its affinity for the SNARE complex and consequently enhance docking of synaptotagmin-7-labeled vesicles with the plasma membrane. This could lead to a change in the apparent calcium sensitivity of exocytosis, as synaptotagmin-7 has a higher calcium affinity than synaptotagmin-1 [127]. Consistent with a scenario under which different synaptotagmin isoforms are relevant PKC targets in different cellular systems, Nagy et al showed in chromaffin cells that overexpression of synaptotagmin-1 phosphomutants and phosphomimetics did not appear to alter exocytosis, whereas in another system, hippocampal neurons, phosphomimetics of synaptotagmin-1 regulate exocytosis [73, 130].…”

“…There is a growing body of evidence to suggest that canonical endocytotic proteins—dynamin, amphiphysin, syndapin, and others—may play a role in modulating fusion pore expansion or collapse via a kiss-and-run mechanism [127, 145–149]. Dynamin and other endocytotic proteins are known to be modulated by PKC activity [150, 151].…”

“…Munc18 also appears to help to regulate the selection of larger diameter vesicles for docking and fusion, and vesicle size directly contributes to fusion pore size [154]. Recent work has implicated synaptotagmin in fusion pore kinetic control [127], though it is not clear how its phosphorylation might affect this putative function. Obviously, lipids play a central role in fusion pore structure and dynamics [155], and Xue et al invoke a lipid-mediated mechanism to account for PKC effects on fusion pore dynamics [144].…”

Different strokes for different synaptotagmins

“…A 2014 study by Anantharam’s group indicated that the two synaptotagmin isoforms expressed in chromaffin cells, synaptotagmin-1 (Syt-1) and Syt-7, are located on distinct populations of chromaffin secretory granules (2). This dovetails with other data showing differences among synaptotagmins.…”