Acid-sensing ion channels in pain and disease

Wemmie, John A.; Taugher, Rebecca J.; Kreple, Collin J.

doi:10.1038/nrn3529

Cited by 527 publications

(614 citation statements)

References 141 publications

(189 reference statements)

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“…ASICs are cation-selective, proton-gated ion channels associated with nociception and other physiological processes and they are a promising target for the treatment of inflammatory pain as well as a range of neurological disorders. [26][27][28][29][30] PcTx1 is a 40-residue peptide with a inhibitory cysteine knot motif isolated from the venom of the tarantula Psalmopoeus cambridgei. It is the most potent and selective blocker of ASIC1 known.…”

Section: Introductionmentioning

confidence: 99%

Combination of Ambiguous and Unambiguous Data in the Restraint-driven Docking of Flexible Peptides with HADDOCK: The Binding of the Spider Toxin PcTx1 to the Acid Sensing Ion Channel (ASIC) 1a

Deplazes

Davies

Bonvin

et al. 2015

J. Chem. Inf. Model.

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Peptides that bind to ion channels have attracted much interest as potential lead molecules for the development of new drugs and insecticides. However, the structure determination of large peptidechannel complexes using experimental methods is challenging. Thus structural models are often derived from combining experimental information with restraint-driven docking approaches. Using the complex formed by the venom peptide PcTx1 and the acid sensing ion channel (ASIC) 1a as a case study, we have examined the effect of different combinations of restraints and input structures on the statistical likelihood of (a) correctly predicting the structure of the binding interface and (b) the ability to predict which residues are involved in specific pairwise peptide-channel interactions. For this, we have analyzed over 200 000 water-refined docked structures obtained with various amounts and types of restraints of the peptidechannel complex predicted using the docking program HADDOCK. We found that increasing the number of restraints or even the use of pairwise interaction data resulted in only a modest improvement in the likelihood of finding a structure within a given accuracy. This suggests that shape complementarity and the force field make a large contribution to the accuracy of the predicted structure. The results also showed that there are large variations in the accuracy of the predicted structure depending on the precise combination of residues used as restraints. Finally, we reflect on the limitations of relying on geometric criteria such as root-mean square deviations to assess the accuracy of docking procedures. We propose that in addition to currently used measures, the likelihood of finding a structure within a given level of accuracy should be also used to evaluate docking methods.

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Section: Introductionmentioning

confidence: 99%

Combination of Ambiguous and Unambiguous Data in the Restraint-driven Docking of Flexible Peptides with HADDOCK: The Binding of the Spider Toxin PcTx1 to the Acid Sensing Ion Channel (ASIC) 1a

Deplazes

Davies

Bonvin

et al. 2015

J. Chem. Inf. Model.

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“…ASICs are Na + -permeable and, to a lesser extent, Ca 2+ -permeable channels that are activated by extracellular acidosis (13)(14)(15)(16)(17)(18)(19). In the brain, ASICs consist of homotrimeric and heterotrimeric complexes of ASIC1a, ASIC2a, and ASIC2b.…”

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confidence: 99%

Protons are a neurotransmitter that regulates synaptic plasticity in the lateral amygdala

Reznikov²,

Price³

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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244

360

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Stimulating presynaptic terminals can increase the proton concentration in synapses. Potential receptors for protons are acidsensing ion channels (ASICs), Na + -and Ca 2+ -permeable channels that are activated by extracellular acidosis. Those observations suggest that protons might be a neurotransmitter. We found that presynaptic stimulation transiently reduced extracellular pH in the amygdala. The protons activated ASICs in lateral amygdala pyramidal neurons, generating excitatory postsynaptic currents. Moreover, both protons and ASICs were required for synaptic plasticity in lateral amygdala neurons. The results identify protons as a neurotransmitter, and they establish ASICs as the postsynaptic receptor. They also indicate that protons and ASICs are a neurotransmitter/ receptor pair critical for amygdala-dependent learning and memory.long-term potentiation | PcTX1 | acid sensing ion channel

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“…The involvement of ASICs has been recognized in an increasing number of physiological and pathophysiological processes ranging from synaptic plasticity and neuronal injury to nociception and mechanoperception (4,5). ASICs therefore emerge as unique pharmacological targets with potential clinical applications in the management of pain, psychiatric disorders, stroke, and neurodegenerative diseases (5).…”

mentioning

confidence: 99%

Mambalgin-1 Pain-relieving Peptide, Stepwise Solid-phase Synthesis, Crystal Structure, and Functional Domain for Acid-sensing Ion Channel 1a Inhibition

Mourier

Salinas

Kessler

et al. 2016

Journal of Biological Chemistry

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Mambalgins are peptides isolated from mamba venom that specifically inhibit a set of acid-sensing ion channels (ASICs) to relieve pain. We show here the first full stepwise solid phase peptide synthesis of mambalgin-1 and confirm the biological activity of the synthetic toxin both in vitro and in vivo. We also report the determination of its three-dimensional crystal structure showing differences with previously described NMR structures. Finally, the functional domain by which the toxin inhibits ASIC1a channels was identified in its loop II and more precisely in the face containing Phe-27, Leu-32, and Leu-34 residues. Moreover, proximity between Leu-32 in mambalgin-1 and Phe-350 in rASIC1a was proposed from double mutant cycle analysis. These data provide information on the structure and on the pharmacophore for ASIC channel inhibition by mambalgins that could have therapeutic value against pain and probably other neurological disorders.

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Acid-sensing ion channels in pain and disease

Cited by 527 publications

References 141 publications

Combination of Ambiguous and Unambiguous Data in the Restraint-driven Docking of Flexible Peptides with HADDOCK: The Binding of the Spider Toxin PcTx1 to the Acid Sensing Ion Channel (ASIC) 1a

Combination of Ambiguous and Unambiguous Data in the Restraint-driven Docking of Flexible Peptides with HADDOCK: The Binding of the Spider Toxin PcTx1 to the Acid Sensing Ion Channel (ASIC) 1a

Protons are a neurotransmitter that regulates synaptic plasticity in the lateral amygdala

Mambalgin-1 Pain-relieving Peptide, Stepwise Solid-phase Synthesis, Crystal Structure, and Functional Domain for Acid-sensing Ion Channel 1a Inhibition

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