title: Ano1, a Ca2+-activated Cl- channel, coordinates contractility in mouse intestine by Ca2+ transient coordination between interstitial cells of Cajal.
abstract: Interstitial cells of Cajal (ICC) are pacemaker cells that generate electrical activity to drive contractility in the gastrointestinal tract via ion channels. Ano1 (Tmem16a), a Ca(2+)-activated Cl(-) channel, is an ion channel expressed in ICC. Genetic deletion of Ano1 in mice resulted in loss of slow waves in smooth muscle of small intestine. In this study, we show that Ano1 is required to maintain coordinated Ca(2+) transients between myenteric ICC (ICC-MY) of small intestine. First, we found spontaneous Ca(2+) transients in ICC-MY in both Ano1 WT and knockout (KO) mice. However, Ca(2+) transients within the ICC-MY network in Ano1 KO mice were uncoordinated, while ICC-MY Ca(2+) transients in Ano1 WT mice were rhythmic and coordinated. To confirm the role of Ano1 in the loss of Ca(2+) transient coordination, we used pharmacological inhibitors of Ano1 activity and shRNA-mediated knock down of Ano1 expression in organotypic cultures of Ano1 WT small intestine. Coordinated Ca(2+) transients became uncoordinated using both these approaches, supporting the conclusion that Ano1 is required to maintain coordination/rhythmicity of Ca(2+) transients. We next determined the effect on smooth muscle contractility using spatiotemporal maps of contractile activity in Ano1 KO and WT tissues. Significantly decreased contractility that appeared to be non-rhythmic and uncoordinated was observed in Ano1 KO jejunum. In conclusion, Ano1 has a previously unidentified role in the regulation of coordinated gastrointestinal smooth muscle function through coordination of Ca(2+) transients in ICC-MY.
authors: Department of Physiology and Biomedical Engineering Enteric NeuroScience Program, Mayo Clinic, Rochester, MN, USA.
authors: Raman Deep
authors: RD
authors: Singh
authors: Department of Physiology and Biomedical Engineering Enteric NeuroScience Program, Mayo Clinic, Rochester, MN, USA.
authors: Simon J
authors: SJ
authors: Gibbons
authors: Department of Physiology and Biomedical Engineering Enteric NeuroScience Program, Mayo Clinic, Rochester, MN, USA.
authors: Siva Arumugam
authors: SA
authors: Saravanaperumal
authors: Auckland Bioengineering Institute, University of Auckland, Auckland, New Zealand.
authors: Peng
authors: P
authors: Du
authors: Department of Physiology and Cell Biology, University of Nevada School of Medicine, Reno, NV, USA.
authors: Grant W
authors: GW
authors: Hennig
authors: Department of Physiology and Biomedical Engineering Enteric NeuroScience Program, Mayo Clinic, Rochester, MN, USA.
authors: Seth T
authors: ST
authors: Eisenman
authors: Department of Physiology and Biomedical Engineering Enteric NeuroScience Program, Mayo Clinic, Rochester, MN, USA.
authors: Amelia
authors: A
authors: Mazzone
authors: Department of Physiology and Biomedical Engineering Enteric NeuroScience Program, Mayo Clinic, Rochester, MN, USA.
authors: Yujiro
authors: Y
authors: Hayashi
authors: Department of Physiology and Biomedical Engineering Enteric NeuroScience Program, Mayo Clinic, Rochester, MN, USA.
authors: Chike
authors: C
authors: Cao
authors: Department of Physiology and Biomedical Engineering Enteric NeuroScience Program, Mayo Clinic, Rochester, MN, USA.
authors: Gary J
authors: GJ
authors: Stoltz
authors: Department of Physiology and Biomedical Engineering Enteric NeuroScience Program, Mayo Clinic, Rochester, MN, USA.
authors: Tamas
authors: T
authors: Ordog
authors: Department of Anatomy, UCSF School of Medicine, San Francisco, CA, USA.
authors: Jason R
authors: JR
authors: Rock
authors: Department of Molecular Genetics and Microbiology Genetics Institute, University of Florida, College of Medicine, Gainesville, FL, USA.
authors: Brian D
authors: BD
authors: Harfe
authors: Department of Physiology and Biomedical Engineering Enteric NeuroScience Program, Mayo Clinic, Rochester, MN, USA.
authors: Joseph H
authors: JH
authors: Szurszewski
authors: Department of Physiology and Biomedical Engineering Enteric NeuroScience Program, Mayo Clinic, Rochester, MN, USA farrugia.gianrico@mayo.edu.
authors: Gianrico
authors: G
authors: Farrugia
mesh_terms: D000818:Animals; D000075369:Anoctamin-1; D002118:Calcium / Q000378:metabolism; D020013:Calcium Signaling; D018118:Chloride Channels / Q000235:genetics / Q000378:metabolism*; D056885:Interstitial Cells of Cajal / Q000378:metabolism* / Q000502:physiology; D007583:Jejunum / Q000378:metabolism* / Q000502:physiology; D051379:Mice; D009119:Muscle Contraction
chemical_list: C531181:ANO1 protein, mouse; D000075369:Anoctamin-1; D018118:Chloride Channels; D002118:Calcium