TMEM16 proteins produce volume-regulated chloride currents that are reduced in mice lacking TMEM16A.
All vertebrate cells regulate their cell volume by activating chloride channels of unknown molecular identity, thereby activating regulatory volume decrease. We show that the Ca(2+)-activated Cl(-) channel TMEM16A together with other TMEM16 proteins are activated by cell swelling through an autocrine mechanism that involves ATP release and binding to purinergic P2Y(2) receptors. TMEM16A channels are activated by ATP through an increase in intracellular Ca(2+) and a Ca(2+)-independent mechanism engaging extracellular-regulated protein kinases (ERK1/2). The ability of epithelial cells to activate a Cl(-) conductance upon cell swelling, and to decrease their cell volume (regulatory volume decrease) was dependent on TMEM16 proteins. Activation of I(Cl,swell) was reduced in the colonic epithelium and in salivary acinar cells from mice lacking expression of TMEM16A. Thus TMEM16 proteins appear to be a crucial component of epithelial volume-regulated Cl(-) channels and may also have a function during proliferation and apoptotic cell death.
Almaça
Joana
J
Institut für Physiologie, Universität Regensburg, Universitätsstrasse 31, D-93053 Regensburg, Germany.
Tian
Yuemin
Y
Aldehni
Fadi
F
Ousingsawat
Jiraporn
J
Kongsuphol
Patthara
P
Rock
Jason R
JR
Harfe
Brian D
BD
Schreiber
Rainer
R
Kunzelmann
Karl
K
D000818:Animals; D000075369:Anoctamin-1; D017209:Apoptosis; D002118:Calcium / Q000378:metabolism; D002460:Cell Line; D045744:Cell Line, Tumor; D002469:Cell Separation; D018118:Chloride Channels / Q000235:genetics* / Q000502:physiology*; D002712:Chlorides / Q000737:chemistry*; D005786:Gene Expression Regulation; D006801:Humans; D008565:Membrane Proteins / Q000235:genetics* / Q000502:physiology*; D051379:Mice; D008822:Mice, Transgenic; D009363:Neoplasm Proteins / Q000235:genetics* / Q000502:physiology*; D018408:Patch-Clamp Techniques; D017434:Protein Structure, Tertiary
C476213:ANO1 protein, human; C531181:ANO1 protein, mouse; D000075369:Anoctamin-1; D018118:Chloride Channels; D002712:Chlorides; D008565:Membrane Proteins; D009363:Neoplasm Proteins; D002118:Calcium