Regulation of alpha1-adrenoceptor-mediated contractions of the uterine artery by protein kinase C: role of the thick- and thin-filament regulatory pathways.
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.
Zhang
Hongying
H
Department of Pharmacology and Physiology, Center for Perinatal Biology, Loma Linda University School of Medicine, Loma Linda, CA 92350, USA.
Zhang
Lubo
L
D000199:Actins / Q000378:metabolism; D000818:Animals; D001158:Arteries; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D005260:Female; D018994:Myosin Light Chains / Q000378:metabolism; D010766:Phosphorylation; D011247:Pregnancy; D011493:Protein Kinase C / Q000502:physiology*; D018340:Receptors, Adrenergic, alpha-1 / Q000502:physiology*; D012756:Sheep; D014599:Uterus / Q000098:blood supply*; D014661:Vasoconstriction
D000199:Actins; D018994:Myosin Light Chains; D018340:Receptors, Adrenergic, alpha-1; D011493:Protein Kinase C; D048049:Extracellular Signal-Regulated MAP Kinases