Abstract

Acid-sensing ion channels (ASICs) are voltage-independent, amiloride-sensitive channels involved in diverse physiological processes ranging from nociception to taste. Despite the importance of ASICs in physiology, we know little about the mechanism of channel activation. Here we show that psalmotoxin activates non-selective and Na(+)-selective currents in chicken ASIC1a at pH 7.25 and 5.5, respectively. Crystal structures of ASIC1a-psalmotoxin complexes map the toxin binding site to the extracellular domain and show how toxin binding triggers an expansion of the extracellular vestibule and stabilization of the open channel pore. At pH 7.25 the pore is approximately 10 Å in diameter, whereas at pH 5.5 the pore is largely hydrophobic and elliptical in cross-section with dimensions of approximately 5 by 7 Å, consistent with a barrier mechanism for ion selectivity. These studies define mechanisms for activation of ASICs, illuminate the basis for dynamic ion selectivity and provide the blueprints for new therapeutic agents.

Links

Publisher Full Text

Authors

Baconguis I, Gouaux E

Institution

Vollum Institute, Oregon Health and Science University, 3181 SW Sam Jackson Park Road, Portland, Oregon 97239, USA.

Source

Nature 489:7416 2012 Sep 20 pg 400-5

MeSH

Animals
Binding Sites
CHO Cells
Cations, Monovalent
Cesium
Chickens
Cricetinae
Crystallography, X-Ray
Hydrogen-Ion Concentration
Ion Channel Gating
Models, Molecular
Nerve Tissue Proteins
Protein Conformation
Protein Subunits
Sequence Deletion
Sodium
Sodium Channels
Spider Venoms
Spiders
Substrate Specificity

Pub Type(s)

Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

22842900