Serum response factor regulates smooth muscle contractility via myotonic dystrophy protein kinases and L-type calcium channels

Serum response factor (SRF) transcriptionally regulates expression of contractile genes in smooth muscle cells (SMC). Lack or decrease of SRF is directly linked to a phenotypic change of SMC, leading to hypomotility of smooth muscle in the gastrointestinal (GI) tract. However, the molecular mechanis...

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Bibliographic Details
Published in:	PloS one 2017-02, Vol.12 (2), p.e0171262-e0171262
Main Authors:	Lee, Moon Young, Park, Chanjae, Ha, Se Eun, Park, Paul J, Berent, Robyn M, Jorgensen, Brian G, Corrigan, Robert D, Grainger, Nathan, Blair, Peter J, Slivano, Orazio J, Miano, Joseph M, Ward, Sean M, Smith, Terence K, Sanders, Kenton M, Ro, Seungil
Format:	Article
Language:	eng
Subjects:	Analysis Animals Binding sites Biology Biology and Life Sciences Blotting, Western Calcium Calcium (intracellular) Calcium channels Calcium channels (L-type) Calcium Channels, L-Type - physiology Calcium signalling Coupling (molecular) Dentistry Dystrophy Female Gastrointestinal system Gastrointestinal tract Gene expression Genes Genetic aspects Genomes Isoforms Kinases Laboratory animals Male Medicine Medicine and Health Sciences Mice Mice, Knockout MicroRNAs Microscopy, Confocal Motility Muscle contraction Muscle Contraction - drug effects Muscle Contraction - physiology Muscle, Smooth - drug effects Muscle, Smooth - physiology Muscle, Smooth - ultrastructure Muscles Musculoskeletal system Myotonic dystrophy Myotonin-Protein Kinase - physiology Neurosciences Physical Sciences Physiology Polymerase Chain Reaction Protein kinase Proteins Proteomics Reduction Research and Analysis Methods Risk factors Rodents Serum response factor Serum Response Factor - physiology Smooth muscle Tamoxifen - pharmacology
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Summary:	Serum response factor (SRF) transcriptionally regulates expression of contractile genes in smooth muscle cells (SMC). Lack or decrease of SRF is directly linked to a phenotypic change of SMC, leading to hypomotility of smooth muscle in the gastrointestinal (GI) tract. However, the molecular mechanism behind SRF-induced hypomotility in GI smooth muscle is largely unknown. We describe here how SRF plays a functional role in the regulation of the SMC contractility via myotonic dystrophy protein kinase (DMPK) and L-type calcium channel CACNA1C. GI SMC expressed Dmpk and Cacna1c genes into multiple alternative transcriptional isoforms. Deficiency of SRF in SMC of Srf knockout (KO) mice led to reduction of SRF-dependent DMPK, which down-regulated the expression of CACNA1C. Reduction of CACNA1C in KO SMC not only decreased intracellular Ca2+ spikes but also disrupted their coupling between cells resulting in decreased contractility. The role of SRF in the regulation of SMC phenotype and function provides new insight into how SMC lose their contractility leading to hypomotility in pathophysiological conditions within the GI tract.
ISSN:	1932-6203 1932-6203