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ERK and p38 MAPK pathways regulate myosin light chain phosphatase and contribute to Ca 2+ sensitization of intestinal smooth muscle contraction
Author(s) -
Ihara E.,
Yu Q.,
Chappellaz M.,
MacDonald J. A.
Publication year - 2015
Publication title -
neurogastroenterology and motility
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.489
H-Index - 105
eISSN - 1365-2982
pISSN - 1350-1925
DOI - 10.1111/nmo.12491
Subject(s) - myosin light chain phosphatase , myosin light chain kinase , mapk/erk pathway , myosin , contractility , rho associated protein kinase , kinase , protein kinase a , phosphorylation , biology , microbiology and biotechnology , medicine , endocrinology
Background Mitogen‐activated protein kinases ( MAPK s), including extracellular signal‐regulated protein kinase (ERK) and p38 MAPK , are known regulators of smooth muscle contractility. The contraction of smooth muscle is mainly regulated by the phosphorylation of regulatory light chains of myosin II ( LC 20), which is driven by the balance between myosin light chain kinase ( MLCK ) and myosin light chain phosphatase ( MLCP ). We hypothesized that one possible mechanism for MAPK ‐dependent modulation of intestinal smooth muscle contractility is via the regulation of MLCP activity. Methods Contractile responses to carbachol ( CC h) and effects of MAPK inhibitors on CC h‐induced contractions were assessed with isolated rat ileal longitudinal smooth muscle strips. Biochemical assessments of MLCP activity and myosin phosphatse targeting subunit ( MYPT 1) and CPI ‐17 phosphorylations were completed. Key Results Treatment of ileal smooth muscle with PD 98059 (10 μ M; MEK inhibitor) or SB 203580 (10 μ M; p38 MAPK inhibitor) significantly inhibited CC h‐induced contractile force. Decreased MLCP activity was observed during sustained contractions induced by CC h; the MLCP activity was recovered by treatment with PD 98059 and SB 203580. However, MYPT 1 (Thr697 and Thr855) and CPI ‐17 (Thr38) phosphorylations were not affected. Application of ML ‐7 ( MLCK inhibitor) during CC h‐induced sustained contraction elicited an MLCP ‐dependent relaxation, the rate of which was accelerated by application of PD 98059 and SB 203580 with proportional changes in LC 20 phosphorylation levels but not MYPT 1 phosphorylation (Thr697 or Thr855). Conclusions & Inferences ERK and p38 MAPK contribute to CC h‐induced sustained contraction in a LC 20 phosphorylation dependent manner. Moreover, both kinases inhibit MLCP activity possibly by a novel mechanism.