A conformation change in the extracellular domain that accompanies desensitization of acid-sensing ion channel (ASIC) 3

Kenneth A. Cushman, Josephine Marsh-Haffner, John Adelman, Edwin W. McCleskey

Research output: Contribution to journalArticle

49 Citations (Scopus)

Abstract

Acid-sensing ion channels (ASICs) are thought to trigger some forms of acid-induced pain and taste, and to contribute to stroke-induced neural damage. After activation by low extracellular pH, different ASICs undergo desensitization on time scales from 0.1 to 10 s. Consistent with a substantial conformation change, desensitization slows dramatically when temperature drops (Askwith, C.C., C.J. Benson, M.J. Welsh, and P.M. Snyder. 2001. PNAS. 98:6459-6463). The nature of this conformation change is unknown, but two studies showed that desensitization rate is altered by mutations on or near the first transmembrane domain (TM1) (Coric, T., P. Zhang, N. Todorovic, and C.M. Canessa. 2003. J. Biol. Chem. 278:45240-45247; Pfister, Y., I. Gautschi, A.-N. Takeda, M. van Bemmelen, S. Kellenberger, and L. Schild. 2006. J. Biol. Chem. 281:11787-11791). Here we show evidence of a specific conformation change associated with desensitization. When mutated from glutamate to cysteine, residue 79, which is some 20 amino acids extracellular to TM1, can be altered by cysteine-modifying reagents when the channel is closed, but not when it is desensitized; thus, desensitization appears to conceal the residue from the extracellular medium. D78 and E79 are a pair of adjacent acidic amino acids that are highly conserved in ASICs yet absent from epithelial Na+ channels, their acid-insensitive relatives. Despite large effects on desensitization by mutations at positions 78 and 79 - including a shift to 10-fold lower proton concentration with the E79A mutant - there are not significant effects on activation.

Original languageEnglish (US)
Pages (from-to)345-350
Number of pages6
JournalJournal of General Physiology
Volume129
Issue number4
DOIs
StatePublished - Apr 2007

Fingerprint

Acid Sensing Ion Channels
Cysteine
Acidic Amino Acids
Epithelial Sodium Channels
Mutation
Acids
Psychologic Desensitization
Protons
Glutamic Acid
Stroke
Amino Acids
Pain
Temperature

ASJC Scopus subject areas

  • Physiology

Cite this

A conformation change in the extracellular domain that accompanies desensitization of acid-sensing ion channel (ASIC) 3. / Cushman, Kenneth A.; Marsh-Haffner, Josephine; Adelman, John; McCleskey, Edwin W.

In: Journal of General Physiology, Vol. 129, No. 4, 04.2007, p. 345-350.

Research output: Contribution to journalArticle

Cushman, Kenneth A. ; Marsh-Haffner, Josephine ; Adelman, John ; McCleskey, Edwin W. / A conformation change in the extracellular domain that accompanies desensitization of acid-sensing ion channel (ASIC) 3. In: Journal of General Physiology. 2007 ; Vol. 129, No. 4. pp. 345-350.
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abstract = "Acid-sensing ion channels (ASICs) are thought to trigger some forms of acid-induced pain and taste, and to contribute to stroke-induced neural damage. After activation by low extracellular pH, different ASICs undergo desensitization on time scales from 0.1 to 10 s. Consistent with a substantial conformation change, desensitization slows dramatically when temperature drops (Askwith, C.C., C.J. Benson, M.J. Welsh, and P.M. Snyder. 2001. PNAS. 98:6459-6463). The nature of this conformation change is unknown, but two studies showed that desensitization rate is altered by mutations on or near the first transmembrane domain (TM1) (Coric, T., P. Zhang, N. Todorovic, and C.M. Canessa. 2003. J. Biol. Chem. 278:45240-45247; Pfister, Y., I. Gautschi, A.-N. Takeda, M. van Bemmelen, S. Kellenberger, and L. Schild. 2006. J. Biol. Chem. 281:11787-11791). Here we show evidence of a specific conformation change associated with desensitization. When mutated from glutamate to cysteine, residue 79, which is some 20 amino acids extracellular to TM1, can be altered by cysteine-modifying reagents when the channel is closed, but not when it is desensitized; thus, desensitization appears to conceal the residue from the extracellular medium. D78 and E79 are a pair of adjacent acidic amino acids that are highly conserved in ASICs yet absent from epithelial Na+ channels, their acid-insensitive relatives. Despite large effects on desensitization by mutations at positions 78 and 79 - including a shift to 10-fold lower proton concentration with the E79A mutant - there are not significant effects on activation.",
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