Journal Article

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

Slivano, Orazio J., Lee, Moon Young, Park, Chanjae, Ro, Seungil, Jorgensen, Brian G., Sanders, Kenton M., Ha, Se Eun, Park, Paul J., Corrigan, Robert D., Berent, Robyn M., Miano, Joseph M., Ward, Sean M., Grainger, Nathan, Blair, Peter J., Smith, Terence K.

2017

Overview

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.

• Publisher: Public Library of Science,Public Library of Science (PLoS)
• Subject: 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