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RECEPTORS AND SIGNAL TRANSDUCTION

Distinct kinases are involved in contraction of cat esophageal and lower esophageal sphincter smooth muscles

¹Department of Medicine, Seoul National University, Bundang Hospital, Seoungnam, Gyeronggi-Do 463-707; ³Department of Medicine, Seoul National University College of Medicine and Liver Research Institute, Seoul, Korea 110-799; ²Department of Medicine, Rhode Island Hospital, and Division of Biology and Medicine, Brown University Medical School, Providence, Rhode Island 02903; and ⁴Smooth Muscle Research Group, University of Calgary, Calgary, Alberta, Canada T2N 4N1

Submitted 12 September 2003 ; accepted in final form 1 April 2004

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 the activation of calmodulin, which requires a high Ca²⁺ concentration, phosphatase inhibition has been invoked to explain contraction at low cytosolic Ca²⁺ levels. The link between activation of the Ca²⁺-independent protein kinase C (PKC) and MLC phosphorylation observed in the esophagus (ESO) (Sohn UD, Cao W, Tang DC, Stull JT, Haeberle JR, Wang CLA, Harnett KM, Behar J, and Biancani P. Am J Physiol Gastrointest Liver Physiol 281: G467–G478, 2001), however, has not been elucidated. We 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, as well as 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 in ESO. The PKC inhibitor chelerythrine and antibodies to PKC, but not antibodies to PKCII, inhibited contraction of ESO but not of 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 mitogen-activated protein (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 in ESO. Contraction of ESO is mediated by activation of PKC, MEK, ERK1/2, and ILK.

protein kinase C; myosin light chain kinase; phosphatase; integrin-linked kinase

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