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Mol Pharmacol
2020 Dec 01;986:695-709. doi: 10.1124/molpharm.120.000012.
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Allosterically Potentiated α7 Nicotinic Acetylcholine Receptors: Reduced Calcium Permeability and Current-Independent Control of Intracellular Calcium.
Miller DR
,
Khoshbouei H
,
Garai S
,
Cantwell LN
,
Stokes C
,
Thakur G
,
Papke RL
.
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The currents of α7 nicotinic acetylcholine receptors activated by acetylcholine (ACh) are brief. The channel has high permeability to calcium relative to monovalent cations and shows inward rectification. It has been previously noted that in the presence of positive allosteric modulators (PAMs), currents through the channels of α7 receptors differ from normal α7 currents both in sensitivity to specific channel blockers and their current-voltage (I-V) relationships, no longer showing inward rectification. Linear I-V functions are often associated with channels lacking calcium permeability, so we measured the I-V functions of α7 receptors activated by ACh when PAMs were bound to the allosteric binding site in the transmembrane domain. Currents were recorded in chloride-free Ringer's solution with low or high concentrations of extracellular calcium to determine the magnitude of the reversal potential shift in the two conditions as well as the I-V relationships. ACh-evoked currents potentiated by the allosteric agonist-PAMs (ago-PAMs) (3aR,4S,9bS)-4-(4-bromophenyl)-3a,4,5,9b-tetrahydro-3H-cyclopenta[c]quinoline-8-sulfonamide (GAT107) and 3-(3,4-difluorophenyl)-N-(1-(6-(4-(pyridin-2-yl)piperazin-1-yl)pyrazin-2-yl)ethyl)propenamide (B-973B) showed reduced inward rectification and calcium-dependent reversal potential shifts decreased by 80%, and 50%, respectively, compared with currents activated by ACh alone, indicative of reduced calcium permeability. Currents potentiated by 3a,4,5,9b-tetrahydro-4-(1-naphthalenyl)-3H-cyclopentan[c]quinoline-8-sulfonamide were also linear and showed no calcium-dependent reversal potential shifts. The ago-PAMs GAT-107 and B-973B stimulated increases in intracellular calcium in stably transfected HEK293 cells. However, these calcium signals were delayed relative to channel activation produced by these agents and were insensitive to the channel blocker mecamylamine. Our results indicate that, although allosterically activated α7 nicotinic ACh receptor may affect intracellular calcium levels, such effects are not likely due to large channel-dependent calcium influx. SIGNIFICANCE STATEMENT: Positive allosteric modulators (PAMs) of α7 nicotinic acetylcholine receptor can increase channel activation by two or more orders of magnitude, raising the concern that, due to the relatively high calcium permeability of α7 receptors activated by acetylcholine alone, such efficacious PAMs may have cytotoxic side effects. We show that PAMs alter the ion conduction pathway and, in general, reduce the calcium permeability of the channels. This supports the hypothesis that α7 effects on intracellular calcium may be independent of channel-mediated calcium influx.
Aickin,
Adjusting for multiple testing when reporting research results: the Bonferroni vs Holm methods.
1996, Pubmed
Aickin,
Adjusting for multiple testing when reporting research results: the Bonferroni vs Holm methods.
1996,
Pubmed
Alexander,
Ric-3 promotes alpha7 nicotinic receptor assembly and trafficking through the ER subcompartment of dendrites.
2010,
Pubmed
Andersen,
Exploring the positive allosteric modulation of human α7 nicotinic receptors from a single-channel perspective.
2016,
Pubmed
Auerbach,
Single-channel currents from acetylcholine receptors in embryonic chick muscle. Kinetic and conductance properties of gaps within bursts.
1984,
Pubmed
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
Bagdas,
New Insights on Neuronal Nicotinic Acetylcholine Receptors as Targets for Pain and Inflammation: A Focus on α7 nAChRs.
2018,
Pubmed
Bertrand,
Mutations at two distinct sites within the channel domain M2 alter calcium permeability of neuronal alpha 7 nicotinic receptor.
1993,
Pubmed
,
Xenbase
Briggs,
Role of channel activation in cognitive enhancement mediated by alpha7 nicotinic acetylcholine receptors.
2009,
Pubmed
,
Xenbase
Castro,
alpha-Bungarotoxin-sensitive hippocampal nicotinic receptor channel has a high calcium permeability.
1995,
Pubmed
Colón-Sáez,
A mutation in the extracellular domain of the α7 nAChR reduces calcium permeability.
2014,
Pubmed
Dajas-Bailador,
Intracellular Ca2+ signals evoked by stimulation of nicotinic acetylcholine receptors in SH-SY5Y cells: contribution of voltage-operated Ca2+ channels and Ca2+ stores.
2002,
Pubmed
Donvito,
The interaction between alpha 7 nicotinic acetylcholine receptor and nuclear peroxisome proliferator-activated receptor-α represents a new antinociceptive signaling pathway in mice.
2017,
Pubmed
Dunckley,
Nicotinic modulation of gene expression in SH-SY5Y neuroblastoma cells.
2006,
Pubmed
Fayuk,
Ca2+ permeability of nicotinic acetylcholine receptors in rat hippocampal CA1 interneurones.
2005,
Pubmed
Feuerbach,
Coupling of human nicotinic acetylcholine receptors alpha 7 to calcium channels in GH3 cells.
2005,
Pubmed
Francis,
Muscle-type nicotinic acetylcholine receptor delta subunit determines sensitivity to noncompetitive inhibitors, while gamma subunit regulates divalent permeability.
1996,
Pubmed
,
Xenbase
Freitas,
Effects of α7 positive allosteric modulators in murine inflammatory and chronic neuropathic pain models.
2013,
Pubmed
Fucile,
Human neuronal threonine-for-leucine-248 alpha 7 mutant nicotinic acetylcholine receptors are highly Ca2+ permeable.
2000,
Pubmed
,
Xenbase
Fucile,
Fractional Ca(2+) current through human neuronal alpha7 nicotinic acetylcholine receptors.
2003,
Pubmed
Garai,
B-973, a Novel α7 nAChR Ago-PAM: Racemic and Asymmetric Synthesis, Electrophysiological Studies, and in Vivo Evaluation.
2018,
Pubmed
,
Xenbase
Gerzanich,
alpha 5 Subunit alters desensitization, pharmacology, Ca++ permeability and Ca++ modulation of human neuronal alpha 3 nicotinic receptors.
1998,
Pubmed
,
Xenbase
Gill,
A series of α7 nicotinic acetylcholine receptor allosteric modulators with close chemical similarity but diverse pharmacological properties.
2012,
Pubmed
,
Xenbase
Goodwin,
Amphetamine and methamphetamine differentially affect dopamine transporters in vitro and in vivo.
2009,
Pubmed
Grønlien,
Distinct profiles of alpha7 nAChR positive allosteric modulation revealed by structurally diverse chemotypes.
2007,
Pubmed
,
Xenbase
Guerra-Álvarez,
Positive allosteric modulation of alpha-7 nicotinic receptors promotes cell death by inducing Ca(2+) release from the endoplasmic reticulum.
2015,
Pubmed
Haghighi,
Neuronal nicotinic acetylcholine receptors are blocked by intracellular spermine in a voltage-dependent manner.
1998,
Pubmed
,
Xenbase
Haghighi,
A molecular link between inward rectification and calcium permeability of neuronal nicotinic acetylcholine alpha3beta4 and alpha4beta2 receptors.
2000,
Pubmed
,
Xenbase
Halevi,
Conservation within the RIC-3 gene family. Effectors of mammalian nicotinic acetylcholine receptor expression.
2003,
Pubmed
,
Xenbase
Hamill,
Multiple conductance states of single acetylcholine receptor channels in embryonic muscle cells.
1981,
Pubmed
Hollmann,
Ca2+ permeability of KA-AMPA--gated glutamate receptor channels depends on subunit composition.
1991,
Pubmed
,
Xenbase
Horenstein,
Critical Molecular Determinants of α7 Nicotinic Acetylcholine Receptor Allosteric Activation: SEPARATION OF DIRECT ALLOSTERIC ACTIVATION AND POSITIVE ALLOSTERIC MODULATION.
2016,
Pubmed
,
Xenbase
Horenstein,
Anti-inflammatory Silent Agonists.
2017,
Pubmed
Hosur,
Gene regulation of alpha4beta2 nicotinic receptors: microarray analysis of nicotine-induced receptor up-regulation and anti-inflammatory effects.
2009,
Pubmed
King,
Ionotropic and Metabotropic Mechanisms of Allosteric Modulation of α7 Nicotinic Receptor Intracellular Calcium.
2018,
Pubmed
Kulkarni,
Microwave-assisted Expeditious and Efficient Synthesis of Cyclopentene Ring-fused Tetrahydroquinoline Derivatives Using Three-component Povarov Reaction.
2013,
Pubmed
Kuryatov,
Mutation causing autosomal dominant nocturnal frontal lobe epilepsy alters Ca2+ permeability, conductance, and gating of human alpha4beta2 nicotinic acetylcholine receptors.
1997,
Pubmed
,
Xenbase
Li,
Characterization of the neuroprotective and toxic effects of alpha7 nicotinic receptor activation in PC12 cells.
1999,
Pubmed
,
Xenbase
Matta,
NACHO Mediates Nicotinic Acetylcholine Receptor Function throughout the Brain.
2017,
Pubmed
Miller,
Methamphetamine regulation of activity and topology of ventral midbrain networks.
2019,
Pubmed
Munro,
The α7 nicotinic ACh receptor agonist compound B and positive allosteric modulator PNU-120596 both alleviate inflammatory hyperalgesia and cytokine release in the rat.
2012,
Pubmed
Newcombe,
Diversity of Nicotinic Acetylcholine Receptor Positive Allosteric Modulators Revealed by Mutagenesis and a Revised Structural Model.
2018,
Pubmed
,
Xenbase
Papke,
Working with OpusXpress: methods for high volume oocyte experiments.
2010,
Pubmed
,
Xenbase
Papke,
Comparative pharmacology of rat and human alpha7 nAChR conducted with net charge analysis.
2002,
Pubmed
,
Xenbase
Papke,
Merging old and new perspectives on nicotinic acetylcholine receptors.
2014,
Pubmed
Papke,
The correction of alpha7 nicotinic acetylcholine receptor concentration-response relationships in Xenopus oocytes.
1998,
Pubmed
,
Xenbase
Peng,
Multiple modes of α7 nAChR noncompetitive antagonism of control agonist-evoked and allosterically enhanced currents.
2013,
Pubmed
,
Xenbase
Quadri,
Macroscopic and Microscopic Activation of α7 Nicotinic Acetylcholine Receptors by the Structurally Unrelated Allosteric Agonist-Positive Allosteric Modulators (ago-PAMs) B-973B and GAT107.
2019,
Pubmed
,
Xenbase
Sitzia,
Voltage- and Temperature-Dependent Allosteric Modulation of α7 Nicotinic Receptors by PNU120596.
2011,
Pubmed
Stokes,
Heteromeric Neuronal Nicotinic Acetylcholine Receptors with Mutant β Subunits Acquire Sensitivity to α7-Selective Positive Allosteric Modulators.
2019,
Pubmed
,
Xenbase
Strecker,
Curare binding and the curare-induced subconductance state of the acetylcholine receptor channel.
1989,
Pubmed
Séguéla,
Molecular cloning, functional properties, and distribution of rat brain alpha 7: a nicotinic cation channel highly permeable to calcium.
1993,
Pubmed
,
Xenbase
Tapia,
Ca2+ permeability of the (alpha4)3(beta2)2 stoichiometry greatly exceeds that of (alpha4)2(beta2)3 human acetylcholine receptors.
2007,
Pubmed
,
Xenbase
Thakur,
Expeditious synthesis, enantiomeric resolution, and enantiomer functional characterization of (4-(4-bromophenyl)-3a,4,5,9b-tetrahydro-3H-cyclopenta[c]quinoline-8-sulfonamide (4BP-TQS): an allosteric agonist-positive allosteric modulator of α7 nicotinic acetylcholine receptors.
2013,
Pubmed
,
Xenbase
Timmermann,
Augmentation of cognitive function by NS9283, a stoichiometry-dependent positive allosteric modulator of α2- and α4-containing nicotinic acetylcholine receptors.
2012,
Pubmed
,
Xenbase
Trautmann,
Tubocurarine, a partial agonist for cholinergic receptors.
1983,
Pubmed
Traynelis,
Glutamate receptor ion channels: structure, regulation, and function.
2010,
Pubmed
Uteshev,
Evaluation of Ca2+ permeability of nicotinic acetylcholine receptors in hypothalamic histaminergic neurons.
2010,
Pubmed
Wallace,
Drug targets for cognitive enhancement in neuropsychiatric disorders.
2011,
Pubmed
Ween,
Alpha3* and alpha 7 nAChR-mediated Ca2+ transient generation in IMR-32 neuroblastoma cells.
2010,
Pubmed
Williams,
Investigation of the molecular mechanism of the α7 nicotinic acetylcholine receptor positive allosteric modulator PNU-120596 provides evidence for two distinct desensitized states.
2011,
Pubmed
,
Xenbase
Williams,
Intrinsically low open probability of α7 nicotinic acetylcholine receptors can be overcome by positive allosteric modulation and serum factors leading to the generation of excitotoxic currents at physiological temperatures.
2012,
Pubmed
,
Xenbase
Williams,
Positive allosteric modulators as an approach to nicotinic acetylcholine receptor-targeted therapeutics: advantages and limitations.
2011,
Pubmed