2009
DOI: 10.1074/jbc.m805302200
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Interaction of the Aromatics Tyr-72/Trp-288 in the Interface of the Extracellular and Transmembrane Domains Is Essential for Proton Gating of Acid-sensing Ion Channels

Abstract: Acid-sensing ion channels are proton-activated ion channels expressed in the nervous system. They belong to the family of ENaC/Degenerins whose members share a conserved structure but are activated by widely diverse stimuli. We show that interaction of two aromatic residues, Tyr-72, located immediately after the first transmembrane segment, and Trp-288, located at the tip of a loop of the extracellular domain directed toward the first transmembrane segment, is essential for proton activation of the acid-sensin… Show more

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Cited by 80 publications
(109 citation statements)
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“…We calculated pK a values Ͻ5 for all His residues. His-72 and His-73 are located on top of the first transmembrane helix, next to Tyr-71 that interacts with Trp-287 of the loop between the thumb and the palm, and they are part of a domain that is highly important for ASIC function (23,43). His-73 is oriented toward and interacts with Asp-78 of a neighboring subunit (for this reason the interaction is not obvious on Fig.…”
Section: Discussionmentioning
confidence: 99%
See 1 more Smart Citation
“…We calculated pK a values Ͻ5 for all His residues. His-72 and His-73 are located on top of the first transmembrane helix, next to Tyr-71 that interacts with Trp-287 of the loop between the thumb and the palm, and they are part of a domain that is highly important for ASIC function (23,43). His-73 is oriented toward and interacts with Asp-78 of a neighboring subunit (for this reason the interaction is not obvious on Fig.…”
Section: Discussionmentioning
confidence: 99%
“…At the lowest position of the loop, Trp-287 points down on Tyr-71 at the extracellular end of the first transmembrane segment. Mutation of Trp-287 or Tyr-71 also affected ASIC pH dependence (43). The finger is located at the uppermost part of the extracellular domain, and its main part contains three short ␣-helices, ␣1-␣3.…”
Section: Discussionmentioning
confidence: 99%
“…Such a model not only accounts for rapid deactivation at pH 8, markedly slower deactivation at pH 7, and the appropriate pH response curve but also harmonizes with existing structural data. Proton activation is thought to proceed from protons binding to pairs of carboxylate residues in the acidic pocket formed by the thumb and finger (53)(54)(55) may also arise from similar pairs in the palm domain (56,57) or elsewhere (60,61). In both regions, carboxylate residues are in close apposition.…”
Section: Discussionmentioning
confidence: 99%
“…To attenuate cooperativity we set out to remove some of ASICs' proton sensors. ASICs are known to have at least two distinct regions of acidic residues implicated in gating (53)(54)(55)(56)(57): the "acidic pocket" formed at interface between the finger and thumb domains as well as the palm domain (Fig. 7A).…”
Section: Mutations To Putative Proton Sensors Attenuate Ph-dependentmentioning
confidence: 99%
“…The respective roles of each of these two H ϩ -binding domains are not yet completely clear. Upon acidification, resulting conformational changes in the extracellular loop are transmitted to the transmembrane domains (23,24), leading to the rapid opening and closing of the channel and to the generation of the transient current. Higher proton concentrations (ϽpH 6.5) also induce conformational changes, generating a very slowly inactivating current, which is associated with a long-lived inactivated state of the channel.…”
Section: Discussionmentioning
confidence: 99%