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Molecular Mechanics of Smooth Muscle Contractile Proteins in Airway Hyperresponsiveness and Asthma

¹ University of Calgary, Faculty of Veterinary Medicine, Calgary, Alberta, Canada; and ² Meakins-Christie Laboratories, McGill University, Montréal, Québec, Canada

Correspondence and requests for reprints should be addressed to Anne-Marie Lauzon, Ph.D., Meakins-Christie Laboratories, McGill University, 3626 St-Urbain street, Montréal, PQ, H2X 2P2 Canada. E-mail: anne-marie.lauzon{at}mcgill.ca

ABSTRACT

Airway hyperresponsiveness (AH) is a hallmark of asthma. The dynamics of the airway smooth muscle (SM) contraction, rather than its force-generating capacity, have been postulated to be key features of AH. Two mechanisms were proposed whereby an increased velocity of shortening (Vmax) of the airway SM leads to excessive bronchoconstriction. The first mechanism involves a greater Vmax during the initial portion of contraction, whereas the second mechanism implicates a greater Vmax after muscle stretches, such as after each tidal breath. This review focuses on the components of the contractile apparatus that have so far been reported to enhance the mechanics of the myosin molecular motor, thus leading to a greater Vmax. A greater activation of myosin, via increased phosphorylation of its regulatory light chain (LC₂₀) by myosin light chain kinase, correlates with an increased Vmax in models of AH and in human asthmatic bronchial SM cells. However, poor correlations between these two parameters have also been reported in other models. A greater expression of the fast SM myosin heavy chain isoform [(+)insert or SM-B] also correlates with the greater Vmax measured in models of AH and in human asthmatic bronchial SM cells. However, the (+)insert isoform can only explain a twofold increase in Vmax, as extrapolated from its velocity of actin filament propulsion in the in vitro motility assay. Further considerations are given to the combination of these two factors with other components of the contractile machinery, thereby leading to the enhancement of airway SM function.

Key Words: thin filament • thick filament • myosin • actin • phosphorylation