Article

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: 42.35). 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.

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    • "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]. "
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    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 · 2.28 Impact Factor
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    • "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. "
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    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 · 4.82 Impact Factor
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    • "Indeed, the possible role of ASICs in the modulation of neuronal network activity during acidosis had not been previously investigated. ASIC1a and ASIC2a can generate functionally heterotrimeric channels that coexist with homotrimeric ASIC1a and homotrimeric ASIC2a channels (Bartoi et al., 2014), and upon proton activation they conduct mostly Na + (Jasti et al., 2007). However, ASIC1a, the human ASIC1b, as well as ASIC1a/2b heterotrimers, also show a Table 1 Comparison of measures of outcome in sham and DA treated mice. "
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    ABSTRACT: Local acidosis is associated with neuro-inflammation and can have significant effects in several neurological disorders, including multiple sclerosis, brain ischemia, spinal cord injury and epilepsy. Despite local acidosis has been implicated in numerous pathological functions, very little is known about the modulatory effects of pathological acidosis on the activity of neuronal networks and on synaptic structural properties. Using non-invasive MRI spectroscopy we revealed protracted extracellular acidosis in the CNS of Experimental Autoimmune Encephalomyelitis (EAE) affected mice. By multi-unit recording in cortical neurons, we established that acidosis affects network activity, down-sizing firing and bursting behaviors as well as amplitudes. Furthermore, a protracted acidosis reduced the number of presynaptic terminals, while it did not affect the postsynaptic compartment. Application of the diarylamidine Diminazene Aceturate (DA) during acidosis significantly reverted both the loss of neuronal firing and bursting and the reduction of presynaptic terminals. Finally, in vivo DA delivery ameliorated the clinical disease course of EAE mice, reducing demyelination and axonal damage. DA is known to block acid-sensing ion channels (ASICs), which are proton-gated, voltage-insensitive, Na(+) permeable channels principally expressed by peripheral and central nervous system neurons. Our data suggest that ASICs activation during acidosis modulates network electrical activity and exacerbates neuro-degeneration in EAE mice. Therefore pharmacological modulation of ASICs in neuroinflammatory diseases could represent a new promising strategy for future therapies aimed at neuro-protection. Copyright © 2014 Elsevier Inc. All rights reserved.
    Brain Behavior and Immunity 12/2014; 45. DOI:10.1016/j.bbi.2014.12.003 · 6.13 Impact Factor
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