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1 Department of Physiology, Queen's University, Kingston, Ontario, Canada
2 Department of Biochemistry, Queen's University, Kingston, Ontario, Canada
3 Department of Physiology, Queen's University, Kingston, Ontario, Canada; Department of Biochemistry, Queen's University, Kingston, Ontario, Canada
* To whom correspondence should be addressed. E-mail: fisherjt{at}post.queensu.ca.
Constitutively active recombinant p21-activated kinase (PAK3) has been shown to induce Ca2+-independent contraction in Triton-skinned phasic ileal smooth muscle, which is accompanied by phosphorylation of caldesmon and desmin (Van Eyk et al. 1998). In the present study, we investigated whether PAK has a broad impact on smooth muscle in general by testing the hypothesis that PAK induces Ca2+-independent contractions and/or Ca2+-sensitization in tonic airway smooth muscle, and that the process is mediated via phosphorylation of caldesmon. In the absence of Ca2+ (pCa >9), constitutively active GST-mPAK3 caused force generation of Triton-skinned canine tracheal smooth muscle (TSM) fibres to approximately 40% of the maximum force generated by Ca2+ at pCa 4.4. In addition, GST-mPAK3 enhanced Ca2+-sensitivity of contraction by increasing force generation by 80% at mid Ca2+ concentrations (pCa 6.2), whereas it had no effect at pCa 4.4. Catalytically inactive GST-mPAK3K297R had no effect on force production. Using antibody against one of the PAK-phosphorylated sites (Ser657) on caldesmon we showed that a basal level of phosphorylation of caldesmon occurs at this site in skinned TSM and that PAK induced-contraction was accompanied by a significant increase in the level of phosphorylation. Western blot analyses show that PAK1 is the predominant PAK isoform expressed in murine, rat, canine and porcine TSM. We conclude that PAK causes Ca2+-independent contractions and produces Ca2+ sensitization of both skinned phasic and tonic smooth muscle, which involves an incremental increase in caldesmon phosphorylation.
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