Premium
Anoctamins and gastrointestinal smooth muscle excitability
Author(s) -
Sanders Kenton M.,
Zhu Mei Hong,
Britton Fiona,
Koh Sang Don,
Ward Sean M.
Publication year - 2012
Publication title -
experimental physiology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.925
H-Index - 101
eISSN - 1469-445X
pISSN - 0958-0670
DOI - 10.1113/expphysiol.2011.058248
Subject(s) - niflumic acid , interstitial cell of cajal , extracellular , chemistry , depolarization , dids , medicine , membrane potential , carbachol , biophysics , endocrinology , microbiology and biotechnology , receptor , biology , biochemistry , membrane , smooth muscle
Interstitial cells of Cajal (ICC) generate electrical pacemaker activity in gastrointestinal smooth muscles. We investigated whether Tmem16a , which encodes anoctamin 1 (ANO1), a Ca 2+ ‐activated Cl − channel, might be involved in pacemaker activity in ICC. The Tmem16a transcripts and ANO1 were expressed robustly in GI muscles, specifically in ICC in murine, non‐human primate ( Macaca fascicularis ) and human GI tracts. Splice variants of Tmem16a , as well as other paralogues of the Tmem16 family, were expressed in gastrointestinal muscles. Calcium‐activated Cl − channel blocking drugs, niflumic acid and DIDS blocked slow waves in intact muscles of mouse, primate and human small intestine and stomach. Slow waves failed to develop in Tmem16a knock‐out mice ( Tmem16a tm1Bdh / tm1Bdh ). The pacemaker mechanism was investigated in isolated ICC from transgenic mice with constitutive expression of copepod super green fluorescent protein (copGFP). Depolarization of ICC activated inward currents due to a Cl − ‐selective conductance. Removal of extracellular Ca 2+ , replacement of Ca 2+ with Ba 2+ , or extracellular Ni 2+ (30 μ m ) blocked the inward current. Single Ca 2+ ‐activated Cl − channels with a unitary conductance of 7.8 pS were resolved in excised patches from ICC. The inward current was blocked in a concentration‐dependent manner by niflumic acid (IC 50 = 4.8 μ m ). The role of ANO1 in cholinergic responses in ICC was also investigated. Carbachol activated Ca 2+ ‐activated Cl − currents in ICC, and responses to cholinergic nerve stimulation were blocked by niflumic acid in intact muscles. Anoctamin 1 is a prominent conductance in ICC, and these channels appear to be involved in pacemaker activity and in responses to enteric excitatory neurotransmitters.