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1 Dept. of Physiology and Graduate Center for Nutritional Sciences, University of Kentucky, Lexington, KY, USA
2 Center for Cell Signaling, University of Virginia, Charlottesville, VA, USA
* To whom correspondence should be addressed. E-mail: mcgong2{at}uky.edu.
CPI-17 (Protein kinase C potentiated phosphatase inhibitor of 17 KD) mediates some agonist-induced smooth muscle contraction by suppressing the myosin phosphatase in a phosphorylation-dependent manner. Physiological relevant kinase(s) that phosphorylate CPI-17 remains to be identified. Several previous studies have shown that some agonist-induced CPI-17 phosphorylation in smooth muscle tissues was attenuated by the Rho kinase (ROCK) inhibitor Y-27632, suggesting ROCK is involved in agonist-induced CPI-17 phosphorylation. However, Y-27632 has recently been found to inhibit protein kinase C
(PKC), a well- recognized CPI-17 kinase. Thus, the role of ROCK in agonist-induced CPI-17 phosphorylation remains uncertain. The current study is designed to address this important issue. We selectively activated the RhoA pathway by inducible adenoviral-mediated expression of a constitutively active mutant RhoA (V14RhoA) in primary cultured rabbit aortic smooth muscle cells (VSMCs). V14RhoA caused expression level-dependent CPI-17 phosphorylation at Thr-38 as well as myosin phosphatase phosphorylation at Thr-853. Importantly, we showed that V14RhoA-induced CPI-17 phosphorylation was not affected by PKC inhibitor GF109203x but was abolished by Y-27632, suggesting that ROCK but not PKC was involved. Further, we showed that contractile agonists, thrombin and U46619, induced CPI-17 phosphorylation in VSMCs. Similar to V14RhoA-induced CPI-17 phosphorylation, thrombin-induced CPI-17 phosphorylation was not affected by inhibition of PKC with GF109203x but was blocked by inhibition of RhoA with adenoviral-mediated expression of exoenzyme C3 as well as by Y-27632. Taken together, we provide the first clear evidence indicating that ROCK is responsible for thrombin- and U-46619-induced CPI-17 phosphorylation in primary cultured VSMCs.
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