Myosin Light Chain Kinase Is Central to Smooth Muscle Contraction and Required for Gastrointestinal Motility in Mice

Wei Qi He, Ya Jing Peng, Wen Cheng Zhang, Ning Lv, Jing Tang, Chen Chen, Cheng Hai Zhang, Song Gao, Hua Qun Chen, Gang Zhi, Robert Feil, Kristine E. Kamm, James T. Stull, Xiang Gao, Min Sheng Zhu

Research output: Contribution to journalArticle

102 Citations (Scopus)

Abstract

Background & Aims: Smooth muscle is essential for maintaining homeostasis for many body functions and provides adaptive responses to stresses imposed by pathologic disorders. Identified cell signaling networks have defined many potential mechanisms for initiating smooth muscle contraction with or without myosin regulatory light chain (RLC) phosphorylation by myosin light chain kinase (MLCK). We generated tamoxifen-inducible and smooth muscle-specific MLCK knockout (KO) mice and provide direct loss-of-function evidence that shows the primary importance of MLCK in phasic smooth muscle contractions. Methods: We used the Cre-loxP system to establish Mlck floxed mice in which exons 23, 24, and 25 were flanked by 2 loxP sites. Smooth muscle-specific MLCK KO mice were generated by crossing Mlck floxed mice with SM-CreERT2 (ki) mice followed by tamoxifen treatment. The phenotype was assessed by histologic, biochemical, molecular, cell biological, and physiologic analyses. Results: Targeted deletion of MLCK in adult mouse smooth muscle resulted in severe gut dysmotility characterized by weak peristalsis, dilation of the digestive tract, and reduction of feces excretion and food intake. There was also abnormal urinary bladder function and lower blood pressure. Isolated muscles showed a loss of RLC phosphorylation and force development induced by K+-depolarization. The kinase knockout also markedly reduced RLC phosphorylation and force development with acetylcholine which activates Ca2+-sensitizing signaling pathways. Conclusions: MLCK and its phosphorylation of RLC are required physiologically for smooth muscle contraction and are essential for normal gastrointestinal motility.

Original languageEnglish (US)
JournalGastroenterology
Volume135
Issue number2
DOIs
StatePublished - Aug 2008

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Myosin-Light-Chain Kinase
Gastrointestinal Motility
Muscle Contraction
Smooth Muscle
Phosphorylation
Smooth Muscle Myosins
Tamoxifen
Light
Knockout Mice
Peristalsis
Myosin Light Chains
Feces
Acetylcholine
Gastrointestinal Tract
Dilatation
Exons
Urinary Bladder
Homeostasis
Phosphotransferases
Eating

ASJC Scopus subject areas

  • Gastroenterology

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Myosin Light Chain Kinase Is Central to Smooth Muscle Contraction and Required for Gastrointestinal Motility in Mice. / He, Wei Qi; Peng, Ya Jing; Zhang, Wen Cheng; Lv, Ning; Tang, Jing; Chen, Chen; Zhang, Cheng Hai; Gao, Song; Chen, Hua Qun; Zhi, Gang; Feil, Robert; Kamm, Kristine E.; Stull, James T.; Gao, Xiang; Zhu, Min Sheng.

In: Gastroenterology, Vol. 135, No. 2, 08.2008.

Research output: Contribution to journalArticle

He, WQ, Peng, YJ, Zhang, WC, Lv, N, Tang, J, Chen, C, Zhang, CH, Gao, S, Chen, HQ, Zhi, G, Feil, R, Kamm, KE, Stull, JT, Gao, X & Zhu, MS 2008, 'Myosin Light Chain Kinase Is Central to Smooth Muscle Contraction and Required for Gastrointestinal Motility in Mice', Gastroenterology, vol. 135, no. 2. https://doi.org/10.1053/j.gastro.2008.05.032
He, Wei Qi ; Peng, Ya Jing ; Zhang, Wen Cheng ; Lv, Ning ; Tang, Jing ; Chen, Chen ; Zhang, Cheng Hai ; Gao, Song ; Chen, Hua Qun ; Zhi, Gang ; Feil, Robert ; Kamm, Kristine E. ; Stull, James T. ; Gao, Xiang ; Zhu, Min Sheng. / Myosin Light Chain Kinase Is Central to Smooth Muscle Contraction and Required for Gastrointestinal Motility in Mice. In: Gastroenterology. 2008 ; Vol. 135, No. 2.
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AU - He, Wei Qi

AU - Peng, Ya Jing

AU - Zhang, Wen Cheng

AU - Lv, Ning

AU - Tang, Jing

AU - Chen, Chen

AU - Zhang, Cheng Hai

AU - Gao, Song

AU - Chen, Hua Qun

AU - Zhi, Gang

AU - Feil, Robert

AU - Kamm, Kristine E.

AU - Stull, James T.

AU - Gao, Xiang

AU - Zhu, Min Sheng

PY - 2008/8

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N2 - Background & Aims: Smooth muscle is essential for maintaining homeostasis for many body functions and provides adaptive responses to stresses imposed by pathologic disorders. Identified cell signaling networks have defined many potential mechanisms for initiating smooth muscle contraction with or without myosin regulatory light chain (RLC) phosphorylation by myosin light chain kinase (MLCK). We generated tamoxifen-inducible and smooth muscle-specific MLCK knockout (KO) mice and provide direct loss-of-function evidence that shows the primary importance of MLCK in phasic smooth muscle contractions. Methods: We used the Cre-loxP system to establish Mlck floxed mice in which exons 23, 24, and 25 were flanked by 2 loxP sites. Smooth muscle-specific MLCK KO mice were generated by crossing Mlck floxed mice with SM-CreERT2 (ki) mice followed by tamoxifen treatment. The phenotype was assessed by histologic, biochemical, molecular, cell biological, and physiologic analyses. Results: Targeted deletion of MLCK in adult mouse smooth muscle resulted in severe gut dysmotility characterized by weak peristalsis, dilation of the digestive tract, and reduction of feces excretion and food intake. There was also abnormal urinary bladder function and lower blood pressure. Isolated muscles showed a loss of RLC phosphorylation and force development induced by K+-depolarization. The kinase knockout also markedly reduced RLC phosphorylation and force development with acetylcholine which activates Ca2+-sensitizing signaling pathways. Conclusions: MLCK and its phosphorylation of RLC are required physiologically for smooth muscle contraction and are essential for normal gastrointestinal motility.

AB - Background & Aims: Smooth muscle is essential for maintaining homeostasis for many body functions and provides adaptive responses to stresses imposed by pathologic disorders. Identified cell signaling networks have defined many potential mechanisms for initiating smooth muscle contraction with or without myosin regulatory light chain (RLC) phosphorylation by myosin light chain kinase (MLCK). We generated tamoxifen-inducible and smooth muscle-specific MLCK knockout (KO) mice and provide direct loss-of-function evidence that shows the primary importance of MLCK in phasic smooth muscle contractions. Methods: We used the Cre-loxP system to establish Mlck floxed mice in which exons 23, 24, and 25 were flanked by 2 loxP sites. Smooth muscle-specific MLCK KO mice were generated by crossing Mlck floxed mice with SM-CreERT2 (ki) mice followed by tamoxifen treatment. The phenotype was assessed by histologic, biochemical, molecular, cell biological, and physiologic analyses. Results: Targeted deletion of MLCK in adult mouse smooth muscle resulted in severe gut dysmotility characterized by weak peristalsis, dilation of the digestive tract, and reduction of feces excretion and food intake. There was also abnormal urinary bladder function and lower blood pressure. Isolated muscles showed a loss of RLC phosphorylation and force development induced by K+-depolarization. The kinase knockout also markedly reduced RLC phosphorylation and force development with acetylcholine which activates Ca2+-sensitizing signaling pathways. Conclusions: MLCK and its phosphorylation of RLC are required physiologically for smooth muscle contraction and are essential for normal gastrointestinal motility.

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