title: Jun kinase-induced overexpression of leukemia-associated Rho GEF (LARG) mediates sustained hypercontraction of longitudinal smooth muscle in inflammation.
abstract: The signaling pathways mediating sustained contraction of mouse colonic longitudinal smooth muscle and the mechanisms involved in hypercontractility of this muscle layer in response to cytokines and TNBS-induced colitis have not been fully explored. In control longitudinal smooth muscle cells, ACh acting via m3 receptors activated sequentially Gα12, RhoGEF (LARG), and the RhoA/Rho kinase pathway. There was abundant expression of MYPT1, minimal expression of CPI-17, and a notable absence of a PKC/CPI-17 pathway. LARG expression was increased in longitudinal muscle cells isolated from muscle strips cultured for 24 h with IL-1β or TNF-α or obtained from the colon of TNBS-treated mice. The increase in LARG expression was accompanied by a significant increase in ACh-stimulated Rho kinase and ZIP kinase activities, and sustained muscle contraction. The increase in LARG expression, Rho kinase and ZIP kinase activities, and sustained muscle contraction was abolished in cells pretreated with the Jun kinase inhibitor, SP600125. Expression of the MLCP activator, telokin, and MLCP activity were also decreased in longitudinal muscle cells from TNBS-treated mice or from strips treated with IL-1β or TNF-α. In contrast, previous studies had shown that sustained contraction in circular smooth muscle is mediated by sequential activation of Gα13, p115RhoGEF, and dual RhoA-dependent pathways involving phosphorylation of MYPT1 and CPI-17. In colonic circular smooth muscle cells isolated from TNBS-treated mice or from strips treated with IL-1β or TNF-α, CPI-17 expression and sustained muscle contraction were decreased. The disparate changes in the two muscle layers contribute to intestinal dysmotility during inflammation.
authors.affiliation: Department of Physiology and Biophysics, VCU Program in Enteric Neuromuscular Sciences, Virginia Commonwealth University, Richmond, Virginia.
authors.forename: Othman
authors.initials: O
authors.lastname: Al-Shboul
authors.affiliation: Department of Physiology and Biophysics, VCU Program in Enteric Neuromuscular Sciences, Virginia Commonwealth University, Richmond, Virginia.
authors.forename: Ancy D
authors.initials: AD
authors.lastname: Nalli
authors.affiliation: Department of Physiology and Biophysics, VCU Program in Enteric Neuromuscular Sciences, Virginia Commonwealth University, Richmond, Virginia.
authors.forename: Divya P
authors.initials: DP
authors.lastname: Kumar
authors.affiliation: Department of Physiology and Biophysics, VCU Program in Enteric Neuromuscular Sciences, Virginia Commonwealth University, Richmond, Virginia.
authors.forename: Ruizhe
authors.initials: R
authors.lastname: Zhou
authors.affiliation: Department of Physiology and Biophysics, VCU Program in Enteric Neuromuscular Sciences, Virginia Commonwealth University, Richmond, Virginia.
authors.forename: Sunila
authors.initials: S
authors.lastname: Mahavadi
authors.affiliation: Department of Physiology and Biophysics, VCU Program in Enteric Neuromuscular Sciences, Virginia Commonwealth University, Richmond, Virginia.
authors.forename: John F
authors.initials: JF
authors.lastname: Kuemmerle
authors.affiliation: Department of Physiology and Biophysics, VCU Program in Enteric Neuromuscular Sciences, Virginia Commonwealth University, Richmond, Virginia.
authors.forename: John R
authors.initials: JR
authors.lastname: Grider
authors.affiliation: Department of Physiology and Biophysics, VCU Program in Enteric Neuromuscular Sciences, Virginia Commonwealth University, Richmond, Virginia skarnam@vcu.edu.
authors.forename: Karnam S
authors.initials: KS
authors.lastname: Murthy
mesh_terms: D000818:Animals; D003092:Colitis / Q000139:chemically induced / Q000378:metabolism* / Q000473:pathology; D003106:Colon / Q000378:metabolism; D064550:Death-Associated Protein Kinases / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects; D007249:Inflammation / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism*; D051379:Mice; D009119:Muscle Contraction / Q000235:genetics; D009130:Muscle, Smooth / Q000378:metabolism* / Q000473:pathology; D009219:Myosin-Light-Chain Kinase / Q000096:biosynthesis; D009924:Organ Culture Techniques; D010446:Peptide Fragments / Q000096:biosynthesis; D010766:Phosphorylation / Q000187:drug effects; D064067:Rho Guanine Nucleotide Exchange Factors / Q000096:biosynthesis* / Q000378:metabolism; D015398:Signal Transduction / Q000235:genetics; D014302:Trinitrobenzenesulfonic Acid / Q000633:toxicity
chemical_list: C577223:Arhgef12 protein, mouse; D010446:Peptide Fragments; D064067:Rho Guanine Nucleotide Exchange Factors; C060640:telokin; D014302:Trinitrobenzenesulfonic Acid; D064550:Death-Associated Protein Kinases; D009219:Myosin-Light-Chain Kinase; D048031:JNK Mitogen-Activated Protein Kinases
keywords: colon; contraction; cytokines; signaling
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