Abstract
Exocytosis proceeds by either full fusion or 'kiss-and-run' between vesicle and plasma membrane. Switching between these two modes permits the cell to regulate the kinetics and amount of secretion. Here we show that ATP receptor activation reduces secretion downstream from cytosolic Ca2+ elevation in rat adrenal chromaffin cells. This reduction is mediated by activation of a pertussis toxin–sensitive Gi/o protein, leading to activation of Gβγ subunits, which promote the 'kiss-and-run' mode by reducing the total open time of the fusion pore during a vesicle fusion event. Furthermore, parallel activation of the muscarinic acetylcholine receptor removes the inhibitory effects of ATP on secretion. This is mediated by a Gq pathway through protein kinase C activation. The inhibitory effects of ATP and its reversal by protein kinase C activation are also shared by opioids and somatostatin. Thus, a variety of G protein pathways exist to modulate Ca2+-evoked secretion at specific steps in fusion pore formation.
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Acknowledgements
We thank C. He for the Gβ1γ2 peptide, Y.T. Wang for the dynamin peptides and I. Bruce for reading the manuscript. This work was supported by grants from the National Basic Research Program of China (G2000077800 and 2006CB500800), the National Natural Science Foundation of China (30330210, 303328013 and C010505 to Z.Z.) and the US National Institutes of Health (DK46564 to C.L.).
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Supplementary information
Supplementary Fig. 1
Dose-response curve of ATP inhibition of quantal size. (PDF 203 kb)
Supplementary Fig. 2
PMA enhances Ca2+-dependent secretion by increasing the number of release events but not quantal size or amperometric spike kinetics. (PDF 484 kb)
Supplementary Fig. 3
PMA inhibits digitonin-induced quantal size in rat adrenal chromaffin cells. (PDF 443 kb)
Supplementary Fig. 4
2-MeS-ATP reduces quantal size of caffeine-induced amperometric spike but has no effect on the caffeine-induced [Ca2+]i signal. (PDF 539 kb)
Supplementary Fig. 5
ATP reduces both quantal size and amperometric spike numbers in depolarization-induced secretion. (PDF 663 kb)
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Chen, XK., Wang, LC., Zhou, Y. et al. Activation of GPCRs modulates quantal size in chromaffin cells through Gβγ and PKC. Nat Neurosci 8, 1160–1168 (2005). https://doi.org/10.1038/nn1529
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DOI: https://doi.org/10.1038/nn1529
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