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 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.
Department of Physiology and Cell Biology, University of Nevada School of Medicine, Reno, Nevada, United States of America.|Department of Physiology, Wonkwang Digestive Disease Research Institute and Institute of Wonkwang Medical Science, School of Medicine, Wonkwang University, Iksan, Chonbuk, Korea.
Moon Young
MY
Lee
Department of Physiology and Cell Biology, University of Nevada School of Medicine, Reno, Nevada, United States of America.
Chanjae
C
Park
Department of Physiology and Cell Biology, University of Nevada School of Medicine, Reno, Nevada, United States of America.
Se Eun
SE
Ha
Department of Physiology and Cell Biology, University of Nevada School of Medicine, Reno, Nevada, United States of America.
Paul J
PJ
Park
Department of Physiology and Cell Biology, University of Nevada School of Medicine, Reno, Nevada, United States of America.
Robyn M
RM
Berent
Department of Physiology and Cell Biology, University of Nevada School of Medicine, Reno, Nevada, United States of America.
Brian G
BG
Jorgensen
Department of Physiology and Cell Biology, University of Nevada School of Medicine, Reno, Nevada, United States of America.
Robert D
RD
Corrigan
Department of Physiology and Cell Biology, University of Nevada School of Medicine, Reno, Nevada, United States of America.
Nathan
N
Grainger
Department of Physiology and Cell Biology, University of Nevada School of Medicine, Reno, Nevada, United States of America.
Peter J
PJ
Blair
Aab Cardiovascular Research Institute, University of Rochester School of Medicine and Dentistry, Rochester, New York, United States of America.
Orazio J
OJ
Slivano
Aab Cardiovascular Research Institute, University of Rochester School of Medicine and Dentistry, Rochester, New York, United States of America.
Joseph M
JM
Miano
Department of Physiology and Cell Biology, University of Nevada School of Medicine, Reno, Nevada, United States of America.
Sean M
SM
Ward
Department of Physiology and Cell Biology, University of Nevada School of Medicine, Reno, Nevada, United States of America.
Terence K
TK
Smith
Department of Physiology and Cell Biology, University of Nevada School of Medicine, Reno, Nevada, United States of America.
Kenton M
KM
Sanders
Department of Physiology and Cell Biology, University of Nevada School of Medicine, Reno, Nevada, United States of America.
Seungil
http://orcid.org/0000-0003-0861-8334
S
Ro
D000818:Animals; D015153:Blotting, Western; D020746:Calcium Channels, L-Type / Q000502:physiology*; D005260:Female; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D018613:Microscopy, Confocal; D009119:Muscle Contraction / Q000187:drug effects / Q000502:physiology*; D009130:Muscle, Smooth / Q000187:drug effects / Q000502:physiology* / Q000648:ultrastructure; D065636:Myotonin-Protein Kinase / Q000502:physiology*; D016133:Polymerase Chain Reaction; D040901:Proteomics; D026362:Serum Response Factor / Q000502:physiology*; D013629:Tamoxifen / Q000494:pharmacology
D020746:Calcium Channels, L-Type; D026362:Serum Response Factor; D013629:Tamoxifen; D065636:Myotonin-Protein Kinase