Modelling of calcium handling in airway myocytes.
Airway myocytes are the primary effectors of airway reactivity which modulates airway resistance and hence ventilation. Stimulation of airway myocytes results in an increase in the cytosolic Ca(2+) concentration ([Ca(2+)](i)) and the subsequent activation of the contractile apparatus. Many contractile agonists, including acetylcholine, induce [Ca(2+)](i) increase via Ca(2+) release from the sarcoplasmic reticulum through InsP(3) receptors. Several models have been developed to explain the characteristics of InsP(3)-induced [Ca(2+)](i) responses, in particular Ca(2+) oscillations. The article reviews the modelling of the major structures implicated in intracellular Ca(2+) handling, i.e., InsP(3) receptors, SERCAs, mitochondria and Ca(2+)-binding cytosolic proteins. We developed theoretical models specifically dedicated to the airway myocyte which include the major mechanisms responsible for intracellular Ca(2+) handling identified in these cells. These biocomputations pointed out the importance of the relative proportion of InsP(3) receptor isoforms and the respective role of the different mechanisms responsible for cytosolic Ca(2+) clearance in the pattern of [Ca(2+)](i) variations. We have developed a theoretical model of membrane conductances that predicts the variations in membrane potential and extracellular Ca(2+) influx. Stimulation of this model by simulated increase in [Ca(2+)](i) predicts membrane depolarisation, but not great enough to trigger a significant opening of voltage-dependant Ca(2+) channels. This may explain why airway contraction induced by cholinergic stimulation does not greatly depend on extracellular calcium. The development of such models of airway myocytes is important for the understanding of the cellular mechanisms of airway reactivity and their possible modulation by pharmacological agents.
Laboratoire de Physiologie Cellulaire Respiratoire, INSERM E 356, Université Victor Segalen Bordeaux 2, 146 rue Léo-Saignat, 33076 Bordeaux cedex, France. etienne.roux@u-bordeaux2.fr
Etienne
E
Roux
Penelope J
PJ
Noble
Denis
D
Noble
Marko
M
Marhl
D000109:Acetylcholine / Q000378:metabolism; D000818:Animals; D002118:Calcium / Q000378:metabolism*; D020013:Calcium Signaling; D006801:Humans; D015544:Inositol 1,4,5-Trisphosphate; D008564:Membrane Potentials; D008928:Mitochondria / Q000502:physiology*; D008954:Models, Biological; D032342:Muscle Cells / Q000502:physiology*; D012137:Respiratory System; D012519:Sarcoplasmic Reticulum / Q000502:physiology*
D015544:Inositol 1,4,5-Trisphosphate; D000109:Acetylcholine; D002118:Calcium