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1 Biochemistry & Molecular Biology, University of Calgary, Calgary, Canada
* To whom correspondence should be addressed. E-mail: jmacdo{at}ucalgary.ca.
We investigated the protein kinases responsible for myosin regulatory light chain (LC20) phosphorylation and regulation of myosin light chain phosphatase (MLCP) activity during microcystin (phosphatase inhibitor)-induced contraction at low [Ca2+] of rat ileal smooth muscle stretched in the longitudinal axis. Application of 1 µM microcystin induced LC20 diphosphorylation and contraction of 
-escin-permeabilized muscle at pCa 9. The PKC inhibitor GF109203x, the MEK inhibitor PD98059, and the p38MAPK inhibitor SB203580 significantly reduced this contraction. These effects were abolished when the microcystin concentration was increased to 10 µM, indicating that application of these kinase inhibitors generated an increase in MLCP activity. GF109203x and PD98059, but not SB203580, decreased MYPT1 (the myosin targeting subunit of MLCP) phosphorylation at Thr-697 (rat sequence) during microcystin-induced contraction at pCa 9. On the other hand, SB203580, but not GF109203x or PD98059, reduced the phosphorylation level of CPI-17. A zipper-interacting protein kinase (ZIPK) inhibitor (SM-1 peptide) and a Rho-associated kinase inhibitor (Y27632) had little effect on microcystin-induced contraction at pCa 9. In conclusion, PKC, ERK1/2 and p38MAPK facilitate microcystin-induced contraction at low [Ca2+] by contributing to the inhibition of MLCP either through phosphorylation of MYPT1 or CPI-17 (probably mediated by integrin-linked kinase (ILK)). ILK and not ZIPK is likely to be the protein kinase responsible for LC20 diphosphorylation during microcystin-induced contraction at pCa 9, similar to its recently described role in vascular smooth muscle. The negative regulation of MLCP by PKC and MAPKs during microcystin-induced contraction at pCa 9 may be unique to phasic smooth muscle.
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