期刊
BIOCHEMICAL JOURNAL
卷 411, 期 -, 页码 543-551出版社
PORTLAND PRESS LTD
DOI: 10.1042/BJ20071299
关键词
gastric muscle; muscle contraction; myosin light chain; nuclear factor kappa B (NF-kappa B) signalling; protein kinase C (PKC)
资金
- NIDDK NIH HHS [DK15564, R01 DK028300, R01 DK015564, DK 28300] Funding Source: Medline
The present study characterized the signalling pathways initiated by the bioactive lipid, LPA (lysophosphatidic acid) in smooth muscle. Expression of LPA(3) receptors, but not LPA, and LPA, receptors was demonstrated by Western blot analysis. LPA stimulated phosphoinositide hydrolysis, PKC (protein kinase Q and Rho kinase (Rho-associated kinase) activities: stimulation of all three enzymes was inhibited by expression of the G(alpha q), but not the G(alpha i), minigene. Initial contraction and MLC20 (20 kDa regulatory light chain of myosin 11) phosphorylation induced by LPA were abolished by inhibitors of PLC (phospholipase C)-beta (U73122) or MLCK (myosin light-chain kinase; ML-9), but were not affected by inhibitors of PKC (bisindolylmaleimide) or Rho kinase (Y27632). In contrast, sustained contraction, and phosphorylation of MLC20 and CPI-17 (PKC-potentiated inhibitor 17 kDa protein) induced by LPA were abolished selectively by bisindolylmaleimide. LPA-induced activation of IKK2 {I kappa B [inhibitor of NF-kappa B (nuclear factor kappa B)] kinase2} and PKA (protein kinase A; cAMP-dependent protein kinase), and degradation Of I kappa B alpha were blocked by the RhoA inhibitor (C3 exoenzyme) and in cells expressing dominant-negative mutants of IKK2(K44A) or RhoA(N19RhoA). Phosphorylation by Rho kinase of MYPT1 (myosin phosphatase targeting subunit 1) at Thr(696) was masked by phosphorylation of MYPT1 at Ser(695) by PKA derived from I kappa B degradation via RhoA, but unmasked in the presence of PKI (PKA inhibitor) or C3 exoenzyme and in cells expressing IKK2(K44A). We conclude that LPA induces initial contraction which involves activation of PLC-beta and MLCK and phosphorylation of MLC20 and sustained contraction which involves activation of PKC and phosphorylation of CPI-17 and MLC20. Although Rho kinase was activated, phosphorylation of MYPT 1 at Thr(696) by Rho kinase was masked by phosphorylation of MYPT1 at Ser(695). via cAMP-independent PKA derived from the NF-kappa B pathway.
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