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Role of Sarcoplasmic Reticulum and Mitochondria in Ca²⁺ Removal in Airway Myocytes

Etienne Roux ^* and Marko Marhl 

^* Laboratoire de Physiologie Cellulaire Respiratoire, Institut National de la Santé et de Recherche Médicale E 356, Université Victor Segalen Bordeaux 2, 33076 Bordeaux, France; and University of Maribor, Department of Physics, Maribor, Slovenia

Correspondence: Address reprint requests to Etienne Roux, Laboratoire de Physiologie Cellulaire Respiratoire, INSERM E 356, Université Victor Segalen Bordeaux 2, 146 Rue Léo-Saignat, 33076 Bordeaux Cedex, France. Tel.: +33-5-57-57-11-31; Fax: +33-5-57-57-16-95; E-mail: etienne.roux{at}u-bordeaux2.fr.

The aim of this study was to use both a theoretical and experimental approach to determine the influence of the sarco-endoplasmic Ca²⁺-ATPase (SERCA) activity and mitochondria Ca²⁺ uptake on Ca²⁺ homeostasis in airway myocytes. Experimental studies were performed on myocytes freshly isolated from rat trachea. [Ca²⁺]_i was measured by microspectrofluorimetry using indo-1. Stimulation by caffeine for 30 s induced a concentration-graded response characterized by a transient peak followed by a progressive decay to a plateau phase. The decay phase was accelerated for 1-s stimulation, indicating ryanodine receptor closure. In Na²⁺-Ca²⁺-free medium containing 0.5 mM La³⁺, the [Ca²⁺]_i response pattern was not modified, indicating no involvement of transplasmalemmal Ca²⁺ fluxes. The mathematical model describing the mechanism of Ca²⁺ handling upon RyR stimulation predicts that after Ca²⁺ release from the sarcoplasmic reticulum, the Ca²⁺ is first sequestrated by cytosolic proteins and mitochondria, and pumped back into the sarcoplasmic reticulum after a time delay. Experimentally, we showed that the [Ca²⁺]_i decay after Ca²⁺ increase was not altered by the SERCA inhibitor cyclopiazonic acid, but was slightly but significantly modified by the mitochondria uncoupler carbonyl cyanide 4-(trifluoromethoxy)phenylhydrazone. The experimental and theoretical results indicate that, although Ca²⁺ pumping back by SERCA is active, it is not primarily involved in [Ca²⁺]_i decrease that is due, in part, to mitochondrial Ca²⁺ uptake.