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Research ArticleArticle

Calcium-Independent Receptor for α-Latrotoxin and Neurexin 1α Facilitate Toxin-Induced Channel Formation: Evidence That Channel Formation Results from Tethering of Toxin to Membrane

Michael D. Hlubek, Edward L. Stuenkel, Valery G. Krasnoperov, Alexander G. Petrenko and Ronald W. Holz
Molecular Pharmacology March 2000, 57 (3) 519-528; DOI: https://doi.org/10.1124/mol.57.3.519
Michael D. Hlubek
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Edward L. Stuenkel
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Valery G. Krasnoperov
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Alexander G. Petrenko
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Ronald W. Holz
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This article has a correction. Please see:

  • Correction - April 01, 2000

Abstract

α-Latrotoxin binding to the calcium-independent receptor for α-latrotoxin (CIRL-1), a putative G-protein-coupled receptor, stimulates secretion from chromaffin and PC12 cells. Using patch clamp techniques and microspectrofluorimetry, we demonstrate that the interaction of α-latrotoxin with CIRL-1 produces a high conductance channel that permits increases in cytosolic Ca2+. α-Latrotoxin interaction with CIRL-1 transiently expressed in bovine chromaffin cells produced a 400-pS channel, which rarely closed under Ca2+-free conditions. The major effect of overexpressing CIRL-1 was to greatly increase the sensitivity of chromaffin cells to channel formation by α-latrotoxin. α-Latrotoxin interaction with CIRL-1 transiently overexpressed in non-neuronal human embryonic kidney 293 (HEK293) cells produced channels that were nearly identical with those observed in chromaffin cells. Channel currents were reduced by millimolar Ca2+. At α-latrotoxin concentrations below 500 pM, channel formation occurred many seconds after binding of toxin to CIRL-1 indicating distinct steps in channel formation. In all cases there was a rapid, sequential addition of channels once the first channel appeared. An analysis of CIRL-1 mutants indicated that channel formation in HEK293 cells is unlikely to be transduced by a G-protein-dependent mechanism. α-Latrotoxin interaction with a fusion construct composed of the extracellular domain of CIRL-1 anchored to the membrane by the transmembrane domain of vesicular stomatitis virus glycoprotein, and with neurexin 1α, an α-latrotoxin receptor structurally unrelated to CIRL-1, produced channels virtually identical with those observed with wild-type CIRL-1. We propose that α-latrotoxin receptors recruit toxin to facilitate its insertion across the membrane and that α-latrotoxin itself controls the conductance properties of the channels it produces.

Footnotes

    • Received July 16, 1999.
    • Accepted November 29, 1999.
  • Send reprint requests to: Dr. Edward Stuenkel, Department of Physiology, University of Michigan Medical School, 7804 MS II, Ann Arbor, MI 48109-0622. E-mail: esterm{at}umich.edu

  • This work was supported by Grants to R.W.H. (RO1DK27959), E.L.S. (NS36227), A.G.P. (NS35098, NS34937), and M.D.H. (American Heart Association of Michigan Postdoctoral Fellowship).

  • The American Society for Pharmacology and Experimental Therapeutics
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Molecular Pharmacology: 57 (3)
Molecular Pharmacology
Vol. 57, Issue 3
1 Mar 2000
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Research ArticleArticle

Calcium-Independent Receptor for α-Latrotoxin and Neurexin 1α Facilitate Toxin-Induced Channel Formation: Evidence That Channel Formation Results from Tethering of Toxin to Membrane

Michael D. Hlubek, Edward L. Stuenkel, Valery G. Krasnoperov, Alexander G. Petrenko and Ronald W. Holz
Molecular Pharmacology March 1, 2000, 57 (3) 519-528; DOI: https://doi.org/10.1124/mol.57.3.519

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Research ArticleArticle

Calcium-Independent Receptor for α-Latrotoxin and Neurexin 1α Facilitate Toxin-Induced Channel Formation: Evidence That Channel Formation Results from Tethering of Toxin to Membrane

Michael D. Hlubek, Edward L. Stuenkel, Valery G. Krasnoperov, Alexander G. Petrenko and Ronald W. Holz
Molecular Pharmacology March 1, 2000, 57 (3) 519-528; DOI: https://doi.org/10.1124/mol.57.3.519
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