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Expression of anoctamin 1/TMEM16A by interstitial cells of Cajal is fundamental for slow wave activity in gastrointestinal muscles
Author(s) -
Hwang Sung Jin,
Blair Peter J. A.,
Britton Fiona C.,
O’Driscoll Kate E.,
Hennig Grant,
Bayguinov Yulia R.,
Rock Jason R.,
Harfe Brian D.,
Sanders Kenton M.,
Ward Sean M.
Publication year - 2009
Publication title -
the journal of physiology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.802
H-Index - 240
eISSN - 1469-7793
pISSN - 0022-3751
DOI - 10.1113/jphysiol.2009.176198
Subject(s) - interstitial cell of cajal , pacemaker potential , niflumic acid , depolarization , biology , chemistry , microbiology and biotechnology , medicine , endocrinology , smooth muscle , biochemistry
Interstitial cells of Cajal (ICC) generate pacemaker activity (slow waves) in gastrointestinal (GI) smooth muscles, but the mechanism(s) of pacemaker activity are controversial. Several conductances, such as Ca 2+ ‐activated Cl − channels (CaCC) and non‐selective cation channels (NSCC) have been suggested to be involved in slow wave depolarization. We investigated the expression and function of a new class of CaCC, anoctamin 1 (ANO1), encoded by Tmem16a , which was discovered to be highly expressed in ICC in a microarray screen. GI muscles express splice variants of the Tmem16a transcript in addition to other paralogues of the Tmem16a family. ANO1 protein is expressed abundantly and specifically in ICC in all regions of the murine, non‐human primate ( Macaca fascicularis ) and human GI tracts. CaCC blocking drugs, niflumic acid and 4,4′‐diisothiocyano‐2,2′‐stillbene‐disulfonic acid (DIDS) reduced the frequency and blocked slow waves in murine, primate, human small intestine and stomach in a concentration‐dependent manner. Unitary potentials, small stochastic membrane depolarizations thought to underlie slow waves, were insensitive to CaCC blockers. Slow waves failed to develop by birth in mice homozygous for a null allele of Tmem16a ( Tmem16a tm1Bdh / tm1Bdh ) and did not develop subsequent to birth in organ culture, as in wildtype and heterozygous muscles. Loss of function of ANO1 did not inhibit the development of ICC networks that appeared structurally normal as indicated by Kit antibodies. These data demonstrate the fundamental role of ANO1 in the generation of slow waves in GI ICC.