The internal calcium store in airway muscle: emptying, refilling and chloride. Possible new directions for drug development.
This review examines the ionic mechanisms underlying acetylcholine (Ach) depolarization of airway smooth muscle and suggests that multiple mechanisms are involved. Increased chloride and nonspecific cation conductance, and decreased or rapidly inactivating potassium conductances seem to be involved. Chloride ions also seem to play an important role in determining whether Ca2+ remains inside or is replenished in the sarcoplasmic reticulum (SR). The physiological role of Ach-induced depolarization is analysed and is suggested to be the promotion of the refilling of Ca2+ stores, partly through a direct refilling of SR-Ca2+ stores by way of an L-type Ca2+ channel. This refilling is promoted by Ca2+ channel agonists and is independent of the transmembrane potential. Ca(2+)-release by a variety of agonists leads to depolarization and stable membrane oscillations which depend on the action of the Ca(2+)-store uptake mechanisms in order to function. These oscillations may play a role in prolonged bronchoconstriction. Better knowledge of the control mechanisms of Cai2+ is likely to reveal new targets for the therapy of asthma and provide a better understanding of the function of airway smooth muscle.
Daniel
E E
EE
McMaster University, Department of Biomedical Sciences, Hamilton, Ontario, Canada.
Bourreau
J P
JP
Abela
A
A
Jury
J
J
D000109:Acetylcholine / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D000818:Animals; D002118:Calcium / Q000378:metabolism*; D018118:Chloride Channels; D002712:Chlorides / Q000378:metabolism*; D015195:Drug Design; D008564:Membrane Potentials; D008565:Membrane Proteins / Q000378:metabolism; D009119:Muscle Contraction / Q000187:drug effects; D009130:Muscle, Smooth / Q000378:metabolism; D009467:Neuromuscular Depolarizing Agents / Q000494:pharmacology; D012137:Respiratory System / Q000378:metabolism*
D018118:Chloride Channels; D002712:Chlorides; D008565:Membrane Proteins; D009467:Neuromuscular Depolarizing Agents; D000109:Acetylcholine; D002118:Calcium