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₁-Adrenoceptor-mediated phosphorylation of MYPT-1 and CPI-17 in the uterine artery: role of ERK/PKC

Center for Perinatal Biology, Department of Pharmacology and Physiology, Loma Linda University School of Medicine, Loma Linda, California

Submitted 29 November 2004 ; accepted in final form 17 January 2005

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/Thr⁶⁹⁶, MYPT-1/Thr⁸⁵⁰, and CPI-17/Thr³⁸ 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 ERK_44/42 and MYPT-1/Thr⁸⁵⁰ that preceded contractions. In addition, phenylephrine induced phosphorylation of CPI-17/Thr³⁸ that was concurrent with the contractions. In contrast, phenylephrine did not induce phosphorylation of MYPT-1/Thr⁶⁹⁶ in the uterine artery. PD-098059 inhibited phosphorylation of ERK_44/42 and the initial peak phosphorylation of MYPT-1/Thr⁸⁵⁰ but did not affect CPI-17/Thr³⁸ 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- and induced a coimmunoprecipitation of PKC- with caldesmon. The results suggest that phosphorylation of MYPT-1/Thr⁸⁵⁰ and CPI-17/Thr³⁸ 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.

myosin light chain phosphatase; phenylephrine; calcium sensitivity; caldesmon

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