Regulation of Alpha1-adrenoceptor-mediated Contractions of the Uterine Artery by Protein Kinase C: Role of the Thick- and Thin-filament Regulatory Pathways.
From: Department of Pharmacology and Physiology, Center for Perinatal Biology, Loma Linda University School of Medicine, Loma Linda, CA 92350, USA.
The Journal of pharmacology and experimental therapeutics
- Publish Date: Sep 2007
- ISSN: 0022-3565
- Volume: 322
- Issue: 3
- Pages: 1253-60
- Medium: Print
- Language: English
- Citation (JAMA): Zhang Hongying, Zhang Lubo, et al. Regulation of Alpha1-adrenoceptor-mediated Contractions of the Uterine Artery by Protein Kinase C: Role of the Thick- and Thin-filament Regulatory Pathways.. J. Pharmacol. Exp. Ther. Sep 2007;322:1253-60
Abstract
Previously we demonstrated that activation of protein kinase C (PKC) enhanced alpha(1)-adrenoceptor-induced contractions in nonpregnant uterine arteries (NPUA) by increasing the Ca(2+) sensitivity but that it inhibited the contractions in pregnant uterine arteries (PUA) by decreasing intracellular Ca(2+) mobilization. The present study tested the hypothesis that PKC activation differentially regulated the thick- and thin-filament regulatory pathways in alpha(1)-adrenoceptor-induced contractions of NPUA and PUA in sheep. Simultaneous measurements of contractions and phosphorylation levels of 20-kDa regulatory myosin light chain (LC(20)) in the same tissue revealed that the PKC activator phorbol-12,13-dibutyrate (PDBu) inhibited phenylephrine-induced phosphorylation of LC(20) and contractions in PUA. In NPUA, PDBu significantly potentiated phenylephrine-induced contractions without significantly changing phosphorylation levels of LC(20). Further studies in NPUA demonstrated that PDBu-mediated potentiation of phenylephrine-induced contractions was associated with a significant increase in phosphorylation levels of extracellular signal-regulated kinase (ERK(42/44)) and caldesmon-Ser(789), measured simultaneously with the tension in the same tissue. In addition, the ERK(42/44) inhibitor PD98059 [2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one] and the actin polymerization inhibitor cytochalasin B produced a concentration-dependent inhibition of PDBu-mediated potentiation of phenylephrine-induced contractions in NPUA. The results suggest that activation of PKC inhibits alpha(1)-adrenoceptor-mediated contractions in PUA through down-regulation of the thick-filament pathway and decreased myosin light chain phosphorylation, but that it enhances the contractions in NPUA through its effect on the thin-filament regulatory pathway and activation of ERK/caldesmon and actin polymerization.
Mesh Headings (Keywords): Actins, Animals, Arteries, Extracellular Signal-Regulated MAP Kinases, Female, Myosin Light Chains, Phosphorylation, Pregnancy, Protein Kinase C, Receptors, Adrenergic, alpha-1, Sheep, Uterus, Vasoconstriction
Check for Full Text / PubMed Unique Identifier (PMID): 17562849
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