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Mol. Biol. Cell 11 (5): 1571-1584

Copyright © 2000 by The American Society for Cell Biology.

Vol. 11, Issue 5, 1571-1584, May 2000

Ca2+ Entry through Store-operated Channels in Mouse Sperm Is Initiated by Egg ZP3 and Drives the Acrosome Reaction

Christine M.B. O'Toole,* Christophe Arnoult,dagger Alberto Darszon,Dagger Richard A. Steinhardt,§ and Harvey M. Florman*||

 *Department of Cell Biology, University of Massachusetts Medical School, Worcester, Massachusetts 01655;  dagger Centre d'Etudes de Grenoble, Departement de Biologie Moleculaire et Structurale, 38054 Grenoble, France;  Dagger Department Genètica y Fisiologìa Molecular, Instituto d Biotecnologia, Cuernavaca, Morelos 62210, Mèxico; and  §Department of Molecular and Cell Biology, University of California, Berkeley, California 94720

Fertilization occurs after the completion of the sperm acrosome reaction, a secretory event that is triggered during gamete adhesion. ZP3, an egg zona pellucida glycoprotein, produces a sustained increase of the internal Ca2+ concentration in mouse sperm, leading to acrosome reactions. Here we show that the sustained Ca2+ concentration increase is due to the persistent activation of a Ca2+ influx mechanism during the late stages of ZP3 signal transduction. These cells also possess a Ca2+ store depletion-activated Ca2+ entry pathway that is open after treatment with thapsigargin. Thapsigargin and ZP3 activate the same Ca2+ permeation mechanism, as demonstrated by fluorescence quenching experiments and by channel antagonists. These studies show that ZP3 generates a sustained Ca2+ influx through a store depletion-operated pathway and that this drives the exocytotic acrosome reaction.

|| Corresponding author. E-mail address: harvey.florman{at}

Molecular Biology of the Cell
Vol. 11, 1571-1584, May 2000
Copyright © 2000 by The American Society for Cell Biology

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   Abstract »    Full Text »    PDF »
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   Abstract »    Full Text »    PDF »
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   Abstract »    Full Text »    PDF »
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   Abstract »    Full Text »    PDF »
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   Abstract »    Full Text »    PDF »
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   Abstract »    Full Text »    PDF »
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   Abstract »    Full Text »    PDF »
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   Abstract »    Full Text »    PDF »
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   Abstract »    Full Text »    PDF »
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   Abstract »    Full Text »    PDF »
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   Abstract »    Full Text »    PDF »
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   Abstract »    Full Text »    PDF »
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   Abstract »    Full Text »    PDF »
Zona pellucida-induced acrosome reaction in human sperm: dependency on activation of pertussis toxin-sensitive Gi protein and extracellular calcium, and priming effect of progesterone and follicular fluid.
A. A. Schuffner, H. S. Bastiaan, H. E. Duran, Z.-Y. Lin, M. Morshedi, D. R. Franken, and S. Oehninger (2002)
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   Abstract »    Full Text »    PDF »
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   Abstract »    Full Text »    PDF »
Motility initiation in herring sperm is regulated by reverse sodium-calcium exchange.
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   Abstract »    Full Text »    PDF »
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   Abstract »    Full Text »    PDF »
An Inositol 1,4,5-Trisphosphate Receptor-Gated Intracellular Ca2+ Store Is Involved in Regulating Sperm Hyperactivated Motility.
H.-C. Ho and S. S. Suarez (2001)
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   Abstract »    Full Text »    PDF »
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   Abstract »    Full Text »    PDF »
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K. Fukami, K. Nakao, T. Inoue, Y. Kataoka, M. Kurokawa, R. A. Fissore, K. Nakamura, M. Katsuki, K. Mikoshiba, N. Yoshida, et al. (2001)
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   Abstract »    Full Text »    PDF »
Motility initiation in herring sperm is regulated by reverse sodium-calcium exchange.
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   Abstract »    Full Text »    PDF »

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