Structure of acid-sensing ion channel 1 at 1.9 A resolution and low pH. Nature

Vollum Institute, Oregon Health and Science University, 3181 SW Sam Jackson Park Road, Portland, Oregon 97239, USA.
Nature (Impact Factor: 41.46). 10/2007; 449(7160):316-23. DOI: 10.1038/nature06163
Source: PubMed

ABSTRACT Acid-sensing ion channels (ASICs) are voltage-independent, proton-activated receptors that belong to the epithelial sodium channel/degenerin family of ion channels and are implicated in perception of pain, ischaemic stroke, mechanosensation, learning and memory. Here we report the low-pH crystal structure of a chicken ASIC1 deletion mutant at 1.9 A resolution. Each subunit of the chalice-shaped homotrimer is composed of short amino and carboxy termini, two transmembrane helices, a bound chloride ion and a disulphide-rich, multidomain extracellular region enriched in acidic residues and carboxyl-carboxylate pairs within 3 A, suggesting that at least one carboxyl group bears a proton. Electrophysiological studies on aspartate-to-asparagine mutants confirm that these carboxyl-carboxylate pairs participate in proton sensing. Between the acidic residues and the transmembrane pore lies a disulphide-rich 'thumb' domain poised to couple the binding of protons to the opening of the ion channel, thus demonstrating that proton activation involves long-range conformational changes.

1 Follower
17 Reads
  • Source
    • "ASICs are proton-gated cation channels with a trimeric subunit arrangement [2]. They are abundant in the central and peripheral nervous systems, where they are involved in mechanosensation [3], nociception [4], memory and learning [5], as well as neurodegenerative disorders, such as ischemic stroke, epilepsy and Parkinson's disease [6]. "
    [Show abstract] [Hide abstract]
    ABSTRACT: ASIC and ENaC are co-expressed in various cell types, and there is evidence for a close association between them. Here, we used atomic force microscopy (AFM) to determine whether ASIC1a and ENaC subunits are able to form cross-clade hybrid ion channels. ASIC1a and ENaC could be co-isolated from detergent extracts of tsA 201 cells co-expressing the two subunits. Isolated proteins were incubated with antibodies against ENaC and Fab fragments against ASIC1a. AFM imaging revealed proteins that were decorated by both an antibody and a Fab fragment with an angle of ∼120° between them, indicating the formation of ASIC1a/ENaC heterotrimers. Copyright © 2015. Published by Elsevier Inc.
    Biochemical and Biophysical Research Communications 05/2015; 464(1). DOI:10.1016/j.bbrc.2015.05.091 · 2.30 Impact Factor
  • Source
    • "Alternatively, PIP 2 may serve as a proton-sensitive ligand . An atomic structure is known for ASIC [37], but the role of PIP 2 in channel activation requires further investigation. Perhaps one reason for a slow adaptation of a " lipid-gating " model for PIP 2 is the fact that the prototypical PIP 2 -gated channel K ir is active during the resting state of excitable cells. "
    [Show abstract] [Hide abstract]
    ABSTRACT: The past decade, membrane signaling lipids emerged as major regulators of ion channel function. However, the molecular nature of lipid binding to ion channels remained poorly described due to a lack of structural information and assays to quantify and measure lipid binding in a membrane. How does a lipid–ligand bind to a membrane protein in the plasma membrane, and what does it mean for a lipid to activate or regulate an ion channel? How does lipid binding compare to activation by soluble neurotransmitter? And how does the cell control lipid agonism? This review focuses on lipids and their interactions with membrane proteins, in particular, ion channels. I discuss the intersection of membrane lipid biology and ion channel biophysics. A picture emerges of membrane lipids as bona fide agonists of ligand-gated ion channels. These freely diffusing signals reside in the plasma membrane, bind to the transmembrane domain of protein, and cause a conformational change that allosterically gates an ion channel. The system employs a catalog of diverse signaling lipids ultimately controlled by lipid enzymes and raft localization. I draw upon pharmacology, recent protein structure, and electrophysiological data to understand lipid regulation and define inward rectifying potassium channels (Kir) as a new class of PIP2 lipid-gated ion channels.
    Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biology of Lipids 01/2015; 1851(5). DOI:10.1016/j.bbalip.2015.01.011 · 5.16 Impact Factor
  • Source
    • "Another possible explanation for the complex phenotypes observed in the knock-out studies would be functional redundancy of the remaining ASICs and/or compensatory effects. Given that ASICs assemble as trimers (Carnally et al., 2008; Jasti et al., 2007) and that ASIC1-4 are expressed in DRG neurons, evidence suggests that different ASIC subunits assemble as heteromers in order to form proton-gated channels in mouse sensory neurons (Benson et al., 2002). Therefore, deletion of one Asic gene could merely change the subunit composition of the remaining trimeric channels , the composition of which will of course depend on expression of ASIC subunits in each sensory neuron sub-type. "
    [Show abstract] [Hide abstract]
    ABSTRACT: It is well established that some members of the Deg/ENaC super family of amiloride sensitive ion channels can participate directly in the transduction of mechanical stimuli by sensory neurons in invertebrates. A large body of work has also implicated the acid sensing ion channels family (ASIC1-4) as participants in regulating mechanoreceptor sensitivity in vertebrates. In this review we provide an overview of the physiological and genetic evidence for involvement of ASICs in mechanosensory function. On balance, the available evidence favors the idea that these channels have an important regulatory role in mechanosensory function. It is striking how diverse the consequences of Asic gene deletion are on mechanosensory function with both gain and loss of function effects being observed depending on sensory neuron type. We conclude that other, as yet unknown, molecular partners of ASIC proteins may be decisive in determining their precise physiological role in mechanosensory neurons. Copyright © 2014. Published by Elsevier Ltd.
    Neuropharmacology 12/2014; 94. DOI:10.1016/j.neuropharm.2014.12.007 · 5.11 Impact Factor
Show more