A new sea anemone peptide, APETx2, inhibits ASIC3, a major acid-sensitive channel in sensory neurons

Authors

  • Sylvie Diochot,

    1. Institut de Pharmacologie Moléculaire et Cellulaire, Centre National de la Recherche Scientifique, Institut Paul Hamel, Valbonne, France
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  • Anne Baron,

    1. Institut de Pharmacologie Moléculaire et Cellulaire, Centre National de la Recherche Scientifique, Institut Paul Hamel, Valbonne, France
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  • Lachlan D Rash,

    1. Institut de Pharmacologie Moléculaire et Cellulaire, Centre National de la Recherche Scientifique, Institut Paul Hamel, Valbonne, France
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  • Emmanuel Deval,

    1. Institut de Pharmacologie Moléculaire et Cellulaire, Centre National de la Recherche Scientifique, Institut Paul Hamel, Valbonne, France
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  • Pierre Escoubas,

    1. Institut de Pharmacologie Moléculaire et Cellulaire, Centre National de la Recherche Scientifique, Institut Paul Hamel, Valbonne, France
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  • Sabine Scarzello,

    1. Institut de Pharmacologie Moléculaire et Cellulaire, Centre National de la Recherche Scientifique, Institut Paul Hamel, Valbonne, France
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  • Miguel Salinas,

    1. Institut de Pharmacologie Moléculaire et Cellulaire, Centre National de la Recherche Scientifique, Institut Paul Hamel, Valbonne, France
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  • Michel Lazdunski

    Corresponding author
    1. Institut de Pharmacologie Moléculaire et Cellulaire, Centre National de la Recherche Scientifique, Institut Paul Hamel, Valbonne, France
    • Corresponding author. Institut de Pharmacologie Moléculaire et Cellulaire, Centre National de la Recherche Scientifique, UMR 6097, Institut Paul Hamel, 660, Route des Lucioles, Sophia Antipolis, 06560 Valbonne, France. Tel.: +33 493 957702 or 03; Fax: +33 493 957704; E-mail: ipmc@ipmc.cnrs.fr

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Abstract

From a systematic screening of animal venoms, we isolated a new toxin (APETx2) from the sea anemone Anthopleura elegantissima, which inhibits ASIC3 homomeric channels and ASIC3-containing heteromeric channels both in heterologous expression systems and in primary cultures of rat sensory neurons. APETx2 is a 42 amino-acid peptide crosslinked by three disulfide bridges, with a structural organization similar to that of other sea anemone toxins that inhibit voltage-sensitive Na+ and K+ channels. APETx2 reversibly inhibits rat ASIC3 (IC50=63 nM), without any effect on ASIC1a, ASIC1b, and ASIC2a. APETx2 directly inhibits the ASIC3 channel by acting at its external side, and it does not modify the channel unitary conductance. APETx2 also inhibits heteromeric ASIC2b+3 current (IC50=117 nM), while it has less affinity for ASIC1b+3 (IC50=0.9 μM), ASIC1a+3 (IC50=2 μM), and no effect on the ASIC2a+3 current. The ASIC3-like current in primary cultured sensory neurons is partly and reversibly inhibited by APETx2 with an IC50 of 216 nM, probably due to the mixed inhibitions of various co-expressed ASIC3-containing channels.

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