Journal
AMERICAN JOURNAL OF PHYSIOLOGY-HEART AND CIRCULATORY PHYSIOLOGY
Volume 288, Issue 6, Pages H2828-H2835Publisher
AMER PHYSIOLOGICAL SOC
DOI: 10.1152/ajpheart.01189.2004
Keywords
myosin light chain phosphatase; phenylephrine; calcium sensitivity; caldesmon
Funding
- NHLBI NIH HHS [HL-57787, HL-67745] Funding Source: Medline
- NICHD NIH HHS [HD-31226] Funding Source: Medline
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We previously demonstrated that ERK/PKC signaling pathways play a key role in regulation of Ca2+ sensitivity and contractility of the uterine artery. The present study tested the hypothesis that ERK and PKC differentially regulated myosin light chain phosphatase activity by phosphorylation of myosin phosphatase target protein-1 (MYPT-1) and CPI-17. Agonist-induced contractions and phosphorylation of MYPT-1/Thr(696), MYPT-1/ Thr(850), and CPI-17/Thr(38) were measured simultaneously in the same tissues of isolated near-term pregnant ovine uterine arteries. Phenylephrine produced time-dependent concurrent increases in the phosphorylation of ERK44/42 and MYPT-1/ Thr(850) that preceded contractions. In addition, phenylephrine induced phosphorylation of CPI-17/ Thr(38) that was concurrent with the contractions. In contrast, phenylephrine did not induce phosphorylation of MYPT-1/ Thr(696) in the uterine artery. PD-098059 inhibited phosphorylation of ERK44/42 and the initial peak phosphorylation of MYPT-1/ Thr(850) but did not affect CPI-17/Thr(38) phosphorylation. Activation of PKC by phorbol 12,13-dibutyrate induced a time-dependent phosphorylation of CPI-17/ Thr38 that preceded contractions of the uterine artery. In addition, phorbol 12,13-dibutyrate activated PKC-alpha and induced a coimmunoprecipitation of PKC-alpha with caldesmon. The results suggest that phosphorylation of MYPT-1/Thr(850) and CPI-17/Thr(38) play important roles in regulation of agonist-mediated Ca2+ sensitivity in the uterine artery, in part by ERK and PKC, respectively. In addition, phosphorylated CPI-17 may regulate Ca2+ sensitivity by interacting with caldesmon and reversing its inhibitory effect on myosin ATPase.
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