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Functional Interaction of Ca_V Channel Isoforms with Ryanodine Receptors Studied in Dysgenic Myotubes

Ralph Peter Schuhmeier ^*, Elodie Gouadon ^*, Daniel Ursu ^*, Nicole Kasielke , Bernhard E. Flucher , Manfred Grabner  and Werner Melzer ^*

^* Department of Applied Physiology, University of Ulm, Ulm, Germany; Department of Physiology and Medical Physics, and Department of Medical Genetics, Molecular and Clinical Pharmacology, Innsbruck Medical University, Innsbruck, Austria

Correspondence: Address reprint requests to Werner Melzer, University of Ulm, Dept. of Applied Physiology, Albert-Einstein-Allee 11, D-89069 Ulm, Germany. Tel.: 49-731-500-23248; Fax: 49-731-500-23260; E-mail: werner.melzer{at}medizin.uni-ulm.de.

The L-type Ca²⁺ channels Ca_V1.1 (_1S) and Ca_V1.2 (_1C) share properties of targeting but differ by their mode of coupling to ryanodine receptors in muscle cells. The brain isoform Ca_V2.1 (_1A) lacks ryanodine receptor targeting. We studied these three isoforms in myotubes of the _1S-deficient skeletal muscle cell line GLT under voltage-clamp conditions and estimated the flux of Ca²⁺ (Ca²⁺ input flux) resulting from Ca²⁺ entry and release. Surprisingly, amplitude and kinetics of the input flux were similar for _1C and _1A despite a previously reported strong difference in responsiveness to extracellular stimulation. The kinetic flux characteristics of _1C and _1A resembled those in _1S-expressing cells but the contribution of Ca²⁺ entry was much larger. _1C but not _1A-expressing cells revealed a distinct transient flux component sensitive to sarcoplasmic reticulum depletion by 30 µM cyclopiazonic acid and 10 mM caffeine. This component likely results from synchronized Ca²⁺-induced Ca²⁺ release that is absent in _1A-expressing myotubes. In cells expressing an _1A-derivative (₁Aas(1592-clip)) containing the putative targeting sequence of _1S, a similar transient component was noticeable. Yet, it was considerably smaller than in _1C, indicating that the local Ca²⁺ entry produced by the chimera is less effective in triggering Ca²⁺ release despite similar global Ca²⁺ inward current density.

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