title: Depression of voltage-activated Ca2+ release in skeletal muscle by activation of a voltage-sensing phosphatase.
abstract: Phosphoinositides act as signaling molecules in numerous cellular transduction processes, and phosphatidylinositol 4,5-bisphosphate (PtdIns(4,5)P2) regulates the function of several types of plasma membrane ion channels. We investigated the potential role of PtdIns(4,5)P2 in Ca(2+) homeostasis and excitation-contraction (E-C) coupling of mouse muscle fibers using in vivo expression of the voltage-sensing phosphatases (VSPs) Ciona intestinalis VSP (Ci-VSP) or Danio rerio VSP (Dr-VSP). Confocal images of enhanced green fluorescent protein-tagged Dr-VSP revealed a banded pattern consistent with VSP localization within the transverse tubule membrane. Rhod-2 Ca(2+) transients generated by 0.5-s-long voltage-clamp depolarizing pulses sufficient to elicit Ca(2+) release from the sarcoplasmic reticulum (SR) but below the range at which VSPs are activated were unaffected by the presence of the VSPs. However, in Ci-VSP-expressing fibers challenged by 5-s-long depolarizing pulses, the Ca(2+) level late in the pulse (3 s after initiation) was significantly lower at 120 mV than at 20 mV. Furthermore, Ci-VSP-expressing fibers showed a reversible depression of Ca(2+) release during trains, with the peak Ca(2+) transient being reduced by ∼30% after the application of 10 200-ms-long pulses to 100 mV. A similar depression was observed in Dr-VSP-expressing fibers. Cav1.1 Ca(2+) channel-mediated current was unaffected by Ci-VSP activation. In fibers expressing Ci-VSP and a pleckstrin homology domain fused with monomeric red fluorescent protein (PLCδ1PH-mRFP), depolarizing pulses elicited transient changes in mRFP fluorescence consistent with release of transverse tubule-bound PLCδ1PH domain into the cytosol; the voltage sensitivity of these changes was consistent with that of Ci-VSP activation, and recovery occurred with a time constant in the 10-s range. Our results indicate that the PtdIns(4,5)P2 level is tightly maintained in the transverse tubule membrane of the muscle fibers, and that VSP-induced depletion of PtdIns(4,5)P2 impairs voltage-activated Ca(2+) release from the SR. Because Ca(2+) release is thought to be independent from InsP3 signaling, the effect likely results from an interaction between PtdIns(4,5)P2 and a protein partner of the E-C coupling machinery.
authors.affiliation: Centre National de la Recherche Scientifique UMR 5534, Université Lyon 1, Centre de Génétique et de Physiologie Moléculaire et Cellulaire, 69100 Villeurbanne, France.
authors.forename: Christine
authors.initials: C
authors.lastname: Berthier
authors.affiliation: Centre National de la Recherche Scientifique UMR 5534, Université Lyon 1, Centre de Génétique et de Physiologie Moléculaire et Cellulaire, 69100 Villeurbanne, France.
authors.forename: Candice
authors.initials: C
authors.lastname: Kutchukian
authors.affiliation: Centre National de la Recherche Scientifique UMR 5534, Université Lyon 1, Centre de Génétique et de Physiologie Moléculaire et Cellulaire, 69100 Villeurbanne, France.
authors.forename: Clément
authors.initials: C
authors.lastname: Bouvard
authors.affiliation: Laboratory of Integrative Physiology, Graduate School of Medicine, Osaka University, Suita, Osaka 565-0871, Japan.
authors.forename: Yasushi
authors.initials: Y
authors.lastname: Okamura
authors.affiliation: Centre National de la Recherche Scientifique UMR 5534, Université Lyon 1, Centre de Génétique et de Physiologie Moléculaire et Cellulaire, 69100 Villeurbanne, France vincent.jacquemond@univ-lyon1.fr.
authors.forename: Vincent
authors.initials: V
authors.lastname: Jacquemond
mesh_terms: D000200:Action Potentials; D000818:Animals; D002118:Calcium / Q000378:metabolism; D020746:Calcium Channels, L-Type / Q000378:metabolism*; D020013:Calcium Signaling; D002478:Cells, Cultured; D051379:Mice; D018485:Muscle Fibers, Skeletal / Q000378:metabolism* / Q000502:physiology; D019269:Phosphatidylinositol 4,5-Diphosphate / Q000378:metabolism; D010744:Phosphoric Monoester Hydrolases / Q000235:genetics / Q000378:metabolism*; D012519:Sarcoplasmic Reticulum / Q000378:metabolism
chemical_list: C529218:CACNA1S protein, mouse; D020746:Calcium Channels, L-Type; D019269:Phosphatidylinositol 4,5-Diphosphate; C509671:voltage-sensor-containing phosphatase, Ciona intestinalis; D010744:Phosphoric Monoester Hydrolases; D002118:Calcium
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