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Protons inhibit anoctamin 1 by competing with calcium

Title
Protons inhibit anoctamin 1 by competing with calcium
Author
김성민
Keywords
Anoctamin 1; ANO1; ANO2; Acid; Secretion; Calcium; E-act
Issue Date
2015-06
Publisher
CHURCHILL LIVINGSTONE
Citation
CELL CALCIUM, v. 58, NO 5, Page. 431-441
Abstract
Cl- efflux through Ca2+-activated Cl- channels (CaCCs) in secretory epithelial cells plays a key role in the regulation of fluid secretion. The fluid and electrolyte secretion is closely related to intracellular pH. CaCCs have been known to be inhibited by intracellular acid. However, the molecular mechanism for the inhibition remains unknown. Anoctamin 1 (ANO1) is a Ca2+-activated Cl- channel that mediates numerous physiological functions including fluid secretion in secretory epithelia. However, little is known about whether ANO1 can be modulated by change of intracellular pH. Here, we demonstrate that Ca2+ induced activation of ANO1 and its homolog ANO2 are strongly inhibited by intracellular acid. Intracellular acid caused a rightward shift of the concentration-response curve of Ca2+ in activating ANO1 and ANO2. To identify the location of the acid-induced inhibition, mutations were made on each of all histidine residues in cytoplasmic part of ANO1. However, none of the His-mutant showed the reduction in the acid-induced inhibition. Furthermore, mutation on Glu- or Asp-residues in the multiple acidic-amino acid regions was ineffective in blocking the acid-induced inhibition. Because the Ca2+-binding site of a fungal anoctamin (nhTMEM16) was uncovered by crystallography, mutagenesis was performed in this region. Surprisingly, mutations at Glu, Asp or Asn residues in the hydrophobic core that are known to be essential for Ca2+-induced activation of ANO1 blocked the acid-induced inhibition. These results suggest that protons interfere with Ca2+ at the Ca2+ binding site of ANO1. These findings provide a molecular mechanism underlying the acid-induced inhibition of ANO1, which may contribute to control fluid and electrolyte secretion in the secretory epithelia. (C) 2015 Published by Elsevier Ltd.
URI
http://www.sciencedirect.com/science/article/pii/S0143416015001141http://hdl.handle.net/20.500.11754/25185
ISSN
0143-4160; 1532-1991
DOI
10.1016/j.ceca.2015.06.011
Appears in Collections:
COLLEGE OF ART AND PHYSICAL EDUCATION[S](예술·체육대학) > PHYSICAL EDUCATION(체육학과) > Articles
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