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Smooth muscle myosin isoform expression and LC₂₀ phosphorylation in innate rat airway hyperresponsiveness

¹Meakins-Christie Laboratories, Department of Medicine, McGill University, and ²Research Center, Sacré-Cur Hospital, Université de Montréal, Montréal, Québec

Submitted 14 September 2004 ; accepted in final form 5 June 2006

Four smooth muscle myosin heavy chain (SMMHC) isoforms are generated by alternative mRNA splicing of a single gene. Two of these isoforms differ by the presence [(+)insert] or absence [(–)insert] of a 7-amino acid insert in the motor domain. The rate of actin filament propulsion of the (+)insert SMMHC isoform, as measured in the in vitro motility assay, is twofold greater than that of the (–)insert isoform. We hypothesized that a greater expression of the (+)insert SMMHC isoform and greater regulatory light chain (LC₂₀) phosphorylation contribute to airway hyperresponsiveness. We measured airway responsiveness to methacholine in Fischer hyperresponsive and Lewis normoresponsive rats and determined SMMHC isoform mRNA and protein expression, as well as essential light chain (LC₁₇) isoforms, h-caldesmon, and -actin protein expression in their tracheae. We also measured tracheal muscle strip contractility in response to methacholine and corresponding LC₂₀ phosphorylation. We found Fischer rats have more (+)insert mRNA (69.4 ± 2.0%) (mean ± SE) than Lewis rats (53.0 ± 2.4%; P < 0.05) and a 44% greater content of (+)insert isoform relative to total myosin protein. No difference was found for LC₁₇ isoform, h-caldesmon, and -actin expression. The contractility experiments revealed a greater isometric force for Fischer trachealis segments (4.2 ± 0.8 mN) than Lewis (1.9 ± 0.4 mN; P < 0.05) and greater LC₂₀ phosphorylation level in Fischer (55.1 ± 6.4) than in Lewis (41.4 ± 6.1; P < 0.05) rats. These results further support the contention that innate airway hyperresponsiveness is a multifactorial disorder in which increased expression of the fast (+)insert SMMHC isoform and greater activation of LC₂₀ lead to smooth muscle hypercontractility.

myosin heavy chain; 7-amino acid insert; phasic muscle; tonic muscle; myosin regulatory light chain; trachealis

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