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1 Department of Medicine, Seoul National University Bundang Hospital, Seoungnam, Gyeronggi-Do, Korea, Democratic People's Rep
2 Medicine, Rhode Island Hospital and Brown Medical School, Providence, RI, USA
3 Department of Medicine, Seoul National University College of Medicine and Liver Research Institute, Seoul, Korea, Democratic People's Rep
4 Smooth Muscle Research Group, University of Calgary, Calgary, Alberta, Canada
* To whom correspondence should be addressed. E-mail: Piero_Biancani{at}brown.edu.
Contraction of smooth muscle depends on the balance of myosin light chain kinase (MLCK) and myosin light chain phosphatase (MLCP) activities. Because MLCK activation depends on activation of calmodulin, which requires a high calcium concentration, phosphatase inhibition has been invoked to explain contraction at low cytosolic calcium levels. The link between activation of the Ca2+-independent PKC
and MLC phosphorylation observed in the esophagus (ESO) (51), however, has not been elucidated. We have used phosphatase and kinase inhibitors and antibodies to signaling enzymes in combination with intact and saponin-permeabilized isolated smooth muscle cells from ESO and lower esophageal sphincter (LES) to examine PKC-dependent, Ca2+-independent signaling in ESO. The phosphatase inhibitors okadaic acid and microcystin-LR, and an antibody to the catalytic subunit of type 1 protein serine/threonine phosphatase, elicited similar contractions in ESO and LES. MLCK inhibitors (ML-7, ML-9 and SM-1) and antibodies to MLCK inhibited contraction induced by phosphatase inhibition in LES, but not ESO. The PKC inhibitor chelerythrine and antibodies to PKC, but not PKC
II, inhibited contraction of ESO, but not LES. In ESO okadaic acid triggered translocation of PKC from cytosolic to particulate fraction, and increased activity of integrin-linked kinase (ILK). Antibodies to the MAP kinases ERK1/ERK2 and to ILK, and the MAP kinase kinase (MEK) inhibitor PD 98059, inhibited okadaic acid-induced ILK activity and contraction of ESO. We conclude that phosphatase inhibition potentiates the effects of MLCK in LES, but not ESO. Contraction of ESO is mediated by activation of PKC, MEK, ERK1/ERK2 and ILK.
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