ArticleMolecular pharmacology2012
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.
Article in Molecular pharmacology, 2012. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 37 papers.
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Who cites it
37 citing papers in PubMed, 60 citations in OpenAlex.
- The efficacy of an allosteric modulator of the alpha 7 nicotinic acetylcholine receptor in a murine model of stroke.Frontiers in neuroscience · 2025Article
- Nicotine: From Discovery to Biological Effects.International journal of molecular sciences · 2023Review
- Differential Activation and Desensitization States Promoted by NoncanonicalThe Journal of pharmacology and experimental therapeutics · 2022Article
- Markov state models of proton- and pore-dependent activation in a pentameric ligand-gated ion channel.eLife · 2021Article
- Probing solution structure of the pentameric ligand-gated ion channel GLIC by small-angle neutron scattering.Proceedings of the National Academy of Sciences of the United States of America · 2021Article
- Therapeutic Targeting ofPharmacological reviews · 2021Review
- Allosterically PotentiatedMolecular pharmacology · 2020Article
- Design, synthesis, and electrophysiological evaluation of NS6740 derivatives: Exploration of the structure-activity relationship for alpha7 nicotinic acetylcholine receptor silent activation.European journal of medicinal chemistry · 2020Article
- Differing Activity Profiles of the Stereoisomers of 2,3,5,6TMP-TQS, a Putative Silent Allosteric Modulator ofMolecular pharmacology · 2020Article
- Nicotinic acetylcholine receptors: Conventional and unconventional ligands and signaling.Neuropharmacology · 2020Review
- Heteromeric Neuronal Nicotinic Acetylcholine Receptors with MutantThe Journal of pharmacology and experimental therapeutics · 2019Article
- Macroscopic and Microscopic Activation ofMolecular pharmacology · 2019Article
- The Antinociceptive and Anti-Inflammatory Properties of theThe Journal of pharmacology and experimental therapeutics · 2018Article
- Pharmacological modulation of the α7 nicotinic acetylcholine receptor in a mouse model of mecamylamine-precipitated nicotine withdrawal.Psychopharmacology · 2018Article
- NS6740, an α7 nicotinic acetylcholine receptor silent agonist, disrupts hippocampal synaptic plasticity.Neuroscience letters · 2018Article
- Ionotropic and Metabotropic Mechanisms of Allosteric Modulation ofMolecular pharmacology · 2018Article
- Nicotinic acetylcholine receptors at the single-channel level.British journal of pharmacology · 2018Review
- Persistent activation of α7 nicotinic ACh receptors associated with stable induction of different desensitized states.British journal of pharmacology · 2018Article
- Effects of α7 Nicotinic Receptor Activation on Cell Survival in Rat Organotypic Hippocampal Slice Cultures.Neurotoxicity research · 2018Article
- New Insights on Neuronal Nicotinic Acetylcholine Receptors as Targets for Pain and Inflammation: A Focus on α7 nAChRs.Current neuropharmacology · 2018Review
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Authors and funding
4 authors at 1 institution in 1 country.
Funding
Abstract
α7 nicotinic acetylcholine receptors (nAChRs) have been a puzzle since their discovery in brain and non-neuronal tissues. Maximal transient probability of an α7 nAChR being open with rapid agonist applications is only 0.002. The concentration dependence of α7 responses measured from transfected cells and Xenopus laevis oocytes shows the same disparity in potency estimations for peak currents and net charge, despite being studied at 1000-fold different time scales. In both cases the EC₅₀ was approximately 10-fold lower for net charge than for peak currents. The equivalence of the data obtained at such disparate time scales indicates that desensitization of α7 is nearly instantaneous. At high levels of agonist occupancy, the receptor is preferentially converted to a ligand-bound nonconducting state, which can be destabilized by the positive allosteric modulator N-(5-chloro-2,4-dimethoxyphenyl)-N'-(5-methyl-3-isoxazolyl)-urea (PNU-120596). Such currents can be sufficiently large to be cytotoxic to the α7-expressing cells. Both the potentiating effect of PNU-120596 and the associated cytotoxicity have a high temperature dependence that can be compensated for by serum factors. Therefore, despite reduced potentiation at body temperatures, use of type II positive allosteric modulators may put cells that naturally express high levels of α7 nAChRs, such as neurons in the hippocampus and hypothalamus, at risk. With a low intrinsic open probability and high propensity toward the induction of nonconducting ligand-bound states, it is likely that the well documented regulation of signal transduction pathways by α7 nAChRs in cells such as those that regulate inflammation may be independent of ion channel activation and associated with the nonconducting conformational states.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.