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J. Biol. Chem., Vol. 281, Issue 9, 5522-5531, March 3, 2006

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-Latrotoxin Induces Exocytosis by Inhibition of Voltage-dependent K⁺ Channels and by Stimulation of L-type Ca²⁺ Channels via Latrophilin in -Cells^*

Sophie Lajus, Pierre Vacher, Denise Huber^¶, Mathilde Dubois, Marie-Noëlle Benassy, Yuri Ushkaryov^||, and Jochen Lang¹

From the Institut Européen de Chimie et Biologie, JE 2390 and INSERM E347, 2 rue Robert Escarpit, 33607 Pessac/Bordeaux, France, the ^¶Centre Médical Universitaire, Université de Genève, 1211 Genève, Switzerland, and the ^||Department of Biological Sciences, Imperial College London, London SW7 2AY, United Kingdom

The spider venom -latrotoxin (-LTX) induces massive exocytosis after binding to surface receptors, and its mechanism is not fully understood. We have investigated its action using toxin-sensitive MIN6 -cells, which express endogenously the -LTX receptor latrophilin (LPH), and toxin-insensitive HIT-T15 -cells, which lack endogenous LPH. -LTX evoked insulin exocytosis in HIT-T15 cells only upon expression of full-length LPH but not of LPH truncated after the first transmembrane domain (LPH-TD1). In HIT-T15 cells expressing full-length LPH and in native MIN6 cells, -LTX first induced membrane depolarization by inhibition of repolarizing K⁺ channels followed by the appearance of Ca²⁺ transients. In a second phase, the toxin induced a large inward current and a prominent increase in intracellular calcium ([Ca²⁺]_i) reflecting pore formation. Upon expression of LPH-TD1 in HIT-T15 cells just this second phase was observed. Moreover, the mutated toxin LTX^N4C, which is devoid of pore formation, only evoked oscillations of membrane potential by reversible inhibition of iberiotoxin-sensitive K⁺ channels via phospholipase C, activated L-type Ca²⁺ channels independently from its effect on membrane potential, and induced an inositol 1,4,5-trisphosphate receptor-dependent release of intracellular calcium in MIN6 cells. The combined effects evoked transient increases in [Ca²⁺]_i in these cells, which were sensitive to inhibitors of phospholipase C, protein kinase C, or L-type Ca²⁺ channels. The latter agents also reduced toxin-induced insulin exocytosis. In conclusion, -LTX induces signaling distinct from pore formation via full-length LPH and phospholipase C to regulate physiologically important K⁺ and Ca²⁺ channels as novel targets of its secretory activity.

Received for publication, September 26, 2005 , and in revised form, November 15, 2005.

^* This work was supported by the Region of Aquitaine and the University of Bordeaux I (Grants BQR2003 and 2004). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ To whom correspondence should be addressed: Tel.: 33-540-00-3349; Fax: 33-540-00-3348; E-mail: j.lang{at}iecb.u-bordeaux.fr.

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