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J Physiol Volume 565, Number 3, 783-799, June 15, 2005 DOI: 10.1113/jphysiol.2005.082586
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{alpha}-Latrotoxin increases spontaneous and depolarization-evoked exocytosis from pancreatic islet ß-cells

Amelia M Silva1, June Liu-Gentry1, Adam S Dickey1, David W Barnett2 and Stanley Misler1

1 Departments of Internal Medicine and Cell Biology/Physiology, Washington University Medical Center, St Louis, MO 63110, USA
2 Department of Biomedical Engineering, Saint Louis University, St Louis, MO, USA

{alpha}-Latrotoxin ({alpha}-LT), a potent excitatory neurotoxin, increases spontaneous, as well as action potential-evoked, quantal release at nerve terminals and increases hormone release from excitable endocrine cells. We have investigated the effects of {alpha}-LT on single human, mouse and canine ß-cells. In isolated and combined measurements, {alpha}-LT, at nanomolar concentrations, induces: (i) rises in cytosolic Ca2+, into the micromolar range, that are dependent on extracellular Ca2+; (ii) large conductance non-selective cation channels; and (iii) Ca2+-dependent insulin granule exocytosis, measured as increases in membrane capacitance and quantal release of preloaded serotonin. Furthermore, at picomolar concentrations, {alpha}-LT potentiates depolarization-induced exocytosis often without evidence of inducing channel activity or increasing cytosolic Ca2+. These results strongly support the hypothesis that {alpha}-LT, after binding to specific receptors, has at least two complementary modes of action on excitable cells. (i) {alpha}-LT inserts into the plasma membrane to form Ca2+ permeable channels and promote Ca2+ entry thereby triggering Ca2+-dependent exocytosis in unstimulated cells. (ii) At lower concentrations, where its channel forming activity is hardly evident, {alpha}-LT augments depolarization-evoked exocytosis probably by second messenger-induced enhancement of the efficiency of the vesicle recruitment or vesicle fusion machinery. We suggest that both modes of action enhance exocytosis from a newly described highly Ca2+-sensitive pool of insulin granules activated by global cytosolic Ca2+ concentrations in the range of ~1 µM.

(Received 4 January 2005; accepted after revision 3 March 2005; first published online 10 March 2005)
Corresponding author S. Misler: Renal Division/Medicine, Box 8126, Washington University Medical Center, St Louis, MO 63110, USA. Email: mislers{at}msnotes.wustl.edu

A. M. Silva, J. Liu-Gentry and A. S. Dickey contributed equally to this work




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S. Lajus, P. Vacher, D. Huber, M. Dubois, M.-N. Benassy, Y. Ushkaryov, and J. Lang
{alpha}-Latrotoxin Induces Exocytosis by Inhibition of Voltage-dependent K+ Channels and by Stimulation of L-type Ca2+ Channels via Latrophilin in beta-Cells
J. Biol. Chem., March 3, 2006; 281(9): 5522 - 5531.
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