Ano1, a Ca2+-activated Cl- channel, coordinates contractility in mouse intestine by Ca2+ transient coordination between interstitial cells of Cajal

Raman Deep Singh, Simon J. Gibbons, Siva Arumugam Saravanaperumal, Peng Du, Grant W. Hennig, Seth T. Eisenman, Amelia Mazzone, Yujiro Hayashi, Chike Cao, Gary J. Stoltz, Tamas Ordog, Jason R. Rock, Brian D. Harfe, Joseph H. Szurszewski, Gianrico Farrugia

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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), aCa2+-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 Ca2+ transients between myenteric ICC (ICC-MY) of small intestine. First, we found spontaneous Ca2+ transients in ICC-MY in both Ano1 WT and knockout (KO) mice. However, Ca2+ transients within the ICC-MY network in Ano1 KO mice were uncoordinated, while ICC-MY Ca2+ transients in Ano1 WT mice were rhythmic and coordinated. To confirm the role of Ano1 in the loss of Ca2+ 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 Ca2+ transients became uncoordinated using both these approaches, supporting the conclusion that Ano1 is required to maintain coordination/rhythmicity of Ca2+ 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 Ca2+ transients in ICC-MY.

Original languageEnglish (US)
Pages (from-to)4051-4068
Number of pages18
JournalJournal of Physiology
Volume592
Issue number18
DOIs
StatePublished - Jan 1 2014

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ASJC Scopus subject areas

  • Physiology

Cite this

Singh, R. D., Gibbons, S. J., Saravanaperumal, S. A., Du, P., Hennig, G. W., Eisenman, S. T., Mazzone, A., Hayashi, Y., Cao, C., Stoltz, G. J., Ordog, T., Rock, J. R., Harfe, B. D., Szurszewski, J. H., & Farrugia, G. (2014). Ano1, a Ca2+-activated Cl- channel, coordinates contractility in mouse intestine by Ca2+ transient coordination between interstitial cells of Cajal. Journal of Physiology, 592(18), 4051-4068. https://doi.org/10.1113/jphysiol.2014.277152