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Ca2+-independent insulin exocytosis induced by alpha-latrotoxin requires latrophilin, a G protein-coupled receptor

Ushkaryov, Y
Grasso, A
Published in EMBO journal. 1998, vol. 17, no. 3, p. 648-57
Abstract alpha-Latrotoxin (alpha-LTX) induces exocytosis of small synaptic vesicles (SSVs) in neuronal cells both by a calcium-independent mechanism and by opening cation-permeable pores. Since the basic molecular events regulating exocytosis in neurons and endocrine cells may be similar, we have used the exocytosis of insulin-containing large dense core vesicles (LDCVs) as a model system. In primary pancreatic beta-cells and in the derived cell lines INS-1 and MIN6, alpha-LTX increased insulin release in the absence of extracellular calcium, but the insulin-secreting cell lines HIT-T15 and RINm5F were unresponsive. alpha-LTX did not alter membrane potential or cytosolic calcium, and its stimulatory effect on exocytosis was still observed in pre-permeabilized INS-1 cells kept at 0.1 microM Ca2+. Consequently, pore formation or ion fluxes induced by alpha-LTX could be excluded. The Ca2+-independent alpha-LTX-binding protein, latrophilin, is a novel member of the secretin family of G protein-coupled receptors (GPCR). Sensitivity to alpha-LTX correlated with expression of latrophilin, but not with synaptotagmin I or neurexin Ialpha expression. Moreover, transient expression of latrophilin in HIT-T15 cells conferred alpha-LTX-induced exocytosis. Our results indicate that direct stimulation of exocytosis by a GPCR mediates the Ca2+-independent effects of alpha-LTX in the absence of altered ion fluxes. Therefore, direct regulation by receptor-activated heterotrimeric G proteins constitutes an important feature of the endocrine exocytosis of insulin-containing LDCVs and may also apply to SSV exocytosis in neurons.
Keywords AnimalsBacterial Toxins/pharmacologyCalcium/pharmacologyCalcium-Binding ProteinsCell LineCell Membrane/drug effects/physiologyCell Membrane Permeability/drug effectsCytosol/chemistry/drug effectsExocytosis/drug effects/physiologyGTP-Binding Proteins/metabolismGene ExpressionGlycoproteinsHemolysin Proteins/pharmacologyInsulin/secretionIslets of Langerhans/metabolism/secretionMembrane Glycoproteins/geneticsMembrane Potentials/drug effectsNerve Tissue Proteins/geneticsNeuropeptidesProtein BindingReceptors, Cell Surface/metabolismReceptors, Peptide/genetics/metabolismSpider Venoms/chemistry/metabolism/pharmacologyStaphylococcus aureus/chemistrySynaptotagmin ISynaptotagmins
PMID: 9450990
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LANG, Jochen et al. Ca2+-independent insulin exocytosis induced by alpha-latrotoxin requires latrophilin, a G protein-coupled receptor. In: EMBO journal, 1998, vol. 17, n° 3, p. 648-57. doi: 10.1093/emboj/17.3.648 https://archive-ouverte.unige.ch/unige:35649

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Deposited on : 2014-04-14

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