Cyclopiazonic acid and thapsigargin reduce Ca2+ influx in frog skeletal muscle fibres as a result of Ca2+ store depletion.
We have investigated the influence of the sarcoplasmic reticulum (SR) Ca2+ content on the retrograde control of skeletal muscle L-type Ca2+ channels activity by ryanodine receptors (RyR). The effects of cyclopiazonic acid (CPA) and thapsigargin (TG), two structurally unrelated inhibitors of SR Ca(2+)-adenosine triphosphatase (ATPase), were examined on the SR Ca2+ content, the calcium current and contraction in single frog semitendinosus fibres using the double mannitol-gap technique. At moderate concentrations that only partially inhibited Ca2+ sequestration by the SR, CPA (2-4 microM) induces a concentration dependent depression of contraction and Ca2+ current amplitudes. When Ba2+ is the charge carrier, the inward current is not changed by CPA suggesting that this Ca(2+)-pump inhibitor does not directly affect dihydropyridine Ca2+ channels. Similar effects were obtained with TG (1-5 microM). Changes in Ca2+ currents and contraction were accompanied by a reduced Ca2+ loading of the SR. We attribute the modulation of the Ca2+ current to the selective inhibition of the SR Ca2+ ATPase, resulting in a decreased Ca2+ release and thereby a reduced activation of calcium inward currents. This is therefore taken to represent a calcium release-dependent modulation of skeletal muscle L-type Ca2+ channels.
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Développement et Physiologie des Structures Contractiles, CNRS UMR 6018, Faculté des Sciences et des Techniques, Nantes, France.
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D000818:Animals; D001464:Barium / Q000493:pharmacokinetics; D002118:Calcium / Q000378:metabolism*; D020746:Calcium Channels, L-Type / Q000378:metabolism; D000252:Calcium-Transporting ATPases / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D066298:In Vitro Techniques; D007211:Indoles / Q000494:pharmacology*; D008564:Membrane Potentials / Q000187:drug effects / Q000502:physiology; D009119:Muscle Contraction / Q000502:physiology; D018485:Muscle Fibers, Skeletal / Q000187:drug effects / Q000378:metabolism*; D018482:Muscle, Skeletal / Q000166:cytology / Q000502:physiology; D018408:Patch-Clamp Techniques; D011893:Rana esculenta; D012519:Sarcoplasmic Reticulum / Q000378:metabolism; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases; D019284:Thapsigargin / Q000494:pharmacology*
D020746:Calcium Channels, L-Type; D004791:Enzyme Inhibitors; D007211:Indoles; D001464:Barium; D019284:Thapsigargin; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases; D000252:Calcium-Transporting ATPases; D002118:Calcium; C000543:cyclopiazonic acid