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J Med Chem
2021 Feb 11;643:1685-1700. doi: 10.1021/acs.jmedchem.0c01973.
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Computational and Functional Mapping of Human and Rat α6β4 Nicotinic Acetylcholine Receptors Reveals Species-Specific Ligand-Binding Motifs.
Hone AJ
,
Kaas Q
,
Kearns I
,
Hararah F
,
Gajewiak J
,
Christensen S
,
Craik DJ
,
McIntosh JM
.
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Nicotinic acetylcholine receptors (nAChRs) are pharmacological targets for the treatment of neuropathic pain, and the α6β4 subtype has been identified as particularly promising. Rat α6β4 nAChRs are less sensitive to some ligands than the human homologue potentially complicating the use of rodent α6β4 receptors for screening therapeutic compounds. We used molecular dynamics simulations coupled with functional assays to study the interaction between α-conotoxin PeIA and α6β4 nAChRs and to identify key ligand-receptor interactions that contribute to species differences in α-conotoxin potency. Our results show that human and rat α6β4 nAChRs have distinct ligand-binding motifs and show markedly different sensitivities to α-conotoxins. These studies facilitated the creation of PeIA-5667, a peptide that shows 270-fold higher potency for rat α6β4 nAChRs over native PeIA and similar potency for the human homologue. Our results may inform the design of therapeutic ligands that target α6β4 nAChRs for the treatment of neuropathic pain.
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33523678
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Azam,
α-Conotoxin BuIA[T5A;P6O]: a novel ligand that discriminates between α6ß4 and α6ß2 nicotinic acetylcholine receptors and blocks nicotine-stimulated norepinephrine release.
2010, Pubmed,
Xenbase
Azam,
α-Conotoxin BuIA[T5A;P6O]: a novel ligand that discriminates between α6ß4 and α6ß2 nicotinic acetylcholine receptors and blocks nicotine-stimulated norepinephrine release.
2010,
Pubmed
,
Xenbase
Azam,
Amino acid residues that confer high selectivity of the alpha6 nicotinic acetylcholine receptor subunit to alpha-conotoxin MII[S4A,E11A,L15A].
2008,
Pubmed
,
Xenbase
Bagdas,
The α7 nicotinic receptor dual allosteric agonist and positive allosteric modulator GAT107 reverses nociception in mouse models of inflammatory and neuropathic pain.
2016,
Pubmed
Bernier,
P2X receptor channels in chronic pain pathways.
2018,
Pubmed
Berta,
Targeting dorsal root ganglia and primary sensory neurons for the treatment of chronic pain.
2017,
Pubmed
Byrd,
Pulsed radiofrequency for chronic pain.
2008,
Pubmed
Dowell,
Alpha-conotoxin PIA is selective for alpha6 subunit-containing nicotinic acetylcholine receptors.
2003,
Pubmed
,
Xenbase
Genzen,
Dorsal root ganglion neurons express multiple nicotinic acetylcholine receptor subtypes.
2001,
Pubmed
Gharpure,
Agonist Selectivity and Ion Permeation in the α3β4 Ganglionic Nicotinic Receptor.
2019,
Pubmed
Giribaldi,
α-Conotoxins to explore the molecular, physiological and pathophysiological functions of neuronal nicotinic acetylcholine receptors.
2018,
Pubmed
Grant,
Proteins for increased surface expression of the α6β4 nicotinic acetylcholine receptor: nothing but good news?
2020,
Pubmed
Hone,
PeIA-5466: A Novel Peptide Antagonist Containing Non-natural Amino Acids That Selectively Targets α3β2 Nicotinic Acetylcholine Receptors.
2019,
Pubmed
,
Xenbase
Hone,
Positional scanning mutagenesis of α-conotoxin PeIA identifies critical residues that confer potency and selectivity for α6/α3β2β3 and α3β2 nicotinic acetylcholine receptors.
2013,
Pubmed
,
Xenbase
Hone,
α-Conotoxin PeIA[S9H,V10A,E14N] potently and selectively blocks α6β2β3 versus α6β4 nicotinic acetylcholine receptors.
2012,
Pubmed
,
Xenbase
Hone,
Nicotinic acetylcholine receptors in neuropathic and inflammatory pain.
2018,
Pubmed
Hone,
α9-containing nicotinic acetylcholine receptors and the modulation of pain.
2018,
Pubmed
Hone,
Nicotinic acetylcholine receptors in dorsal root ganglion neurons include the α6β4* subtype.
2012,
Pubmed
Hone,
α-Conotoxins Identify the α3β4* Subtype as the Predominant Nicotinic Acetylcholine Receptor Expressed in Human Adrenal Chromaffin Cells.
2015,
Pubmed
,
Xenbase
Hone,
Molecular determinants of α-conotoxin potency for inhibition of human and rat α6β4 nicotinic acetylcholine receptors.
2018,
Pubmed
,
Xenbase
Hopkins,
Long-Time-Step Molecular Dynamics through Hydrogen Mass Repartitioning.
2015,
Pubmed
Jin,
Conotoxins: Chemistry and Biology.
2019,
Pubmed
Knowland,
Functional α6β4 acetylcholine receptor expression enables pharmacological testing of nicotinic agonists with analgesic properties.
2020,
Pubmed
Kuryatov,
Human alpha6 AChR subtypes: subunit composition, assembly, and pharmacological responses.
2000,
Pubmed
,
Xenbase
Limapichat,
Subtype-specific mechanisms for functional interaction between α6β4* nicotinic acetylcholine receptors and P2X receptors.
2014,
Pubmed
,
Xenbase
Maier,
ff14SB: Improving the Accuracy of Protein Side Chain and Backbone Parameters from ff99SB.
2015,
Pubmed
Marucci,
Update on novel purinergic P2X3 and P2X2/3 receptor antagonists and their potential therapeutic applications.
2019,
Pubmed
McIntosh,
Analogs of alpha-conotoxin MII are selective for alpha6-containing nicotinic acetylcholine receptors.
2004,
Pubmed
,
Xenbase
McIntosh,
A novel alpha-conotoxin, PeIA, cloned from Conus pergrandis, discriminates between rat alpha9alpha10 and alpha7 nicotinic cholinergic receptors.
2005,
Pubmed
,
Xenbase
Mohammadi,
α9-nicotinic acetylcholine receptors contribute to the maintenance of chronic mechanical hyperalgesia, but not thermal or mechanical allodynia.
2014,
Pubmed
Prashanth,
Pharmacology of predatory and defensive venom peptides in cone snails.
2017,
Pubmed
Pucci,
Engineering of α-conotoxin MII-derived peptides with increased selectivity for native α6β2* nicotinic acetylcholine receptors.
2011,
Pubmed
Ray,
Comparative transcriptome profiling of the human and mouse dorsal root ganglia: an RNA-seq-based resource for pain and sensory neuroscience research.
2018,
Pubmed
Romero,
Inhibition of α9α10 nicotinic acetylcholine receptors prevents chemotherapy-induced neuropathic pain.
2017,
Pubmed
Shen,
Statistical potential for assessment and prediction of protein structures.
2006,
Pubmed
Webb,
Comparative Protein Structure Modeling Using MODELLER.
2016,
Pubmed
Wieskopf,
The nicotinic α6 subunit gene determines variability in chronic pain sensitivity via cross-inhibition of P2X2/3 receptors.
2015,
Pubmed
Wu,
α-Conotoxin [S9A]TxID Potently Discriminates between α3β4 and α6/α3β4 Nicotinic Acetylcholine Receptors.
2017,
Pubmed
,
Xenbase
Zhang,
Nicotine Evoked Currents in Human Primary Sensory Neurons.
2019,
Pubmed
