The nicotinic acetylcholine receptor: From molecular biology to cognition

Changeux, Jean-Pierre; Corringer, Pierre‐Jean; Maskos, Uwe

doi:10.1016/j.neuropharm.2015.03.024

Cited by 32 publications

(35 citation statements)

References 16 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Nicotinic endplate acetylcholine receptors (AChRs) mediate synaptic transmission between vertebrate nerve and skeletal muscle (Ashcroft, 2000;Changeux and Edelstein, 2005). The CRC methods I describe are based on the experimental observation that, in these receptors, affinity and efficacy are not independent (4) (Jadey and Auerbach, 2012).…”

Section: Introductionmentioning

confidence: 99%

Dose–Response Analysis When There Is a Correlation between Affinity and Efficacy

Auerbach

2015

Mol Pharmacol

View full text Add to dashboard Cite

The shape of a concentration-response curve (CRC) is determined by underlying equilibrium constants for agonist binding and receptor conformational change. Typically, agonists are characterized by the empirical CRC parameters efficacy (the maximum response), EC 50 (the concentration that produces a half-maximum response), and the Hill coefficient (the maximum slope of the response). Ligands activate receptors because they bind with higher affinity to the active versus resting conformation, and in skeletal muscle nicotinic acetylcholine receptors there is an exponential relationship between these two equilibrium dissociation constants. Consequently, knowledge of two receptor-specific, agonist-independent constants-the activation equilibrium constant without agonists (E 0 ) and the affinity-correlation exponent (M)-allows an entire CRC to be calculated from a measurement of either efficacy or affinity. I describe methods for estimating the CRCs of partial agonists in receptors that have a correlation between affinity and efficacy.

show abstract

Section: Introductionmentioning

confidence: 99%

Dose–Response Analysis When There Is a Correlation between Affinity and Efficacy

Auerbach

2015

Mol Pharmacol

View full text Add to dashboard Cite

show abstract

“…Understanding their function at an atomic level of detail is likely to be useful for the development of drug therapies against a range of disorders, including nicotine addiction, Alzheimer's disease, schizophrenia, and depression (2).…”

mentioning

confidence: 99%

“…Several kinetic models have been proposed for the processes of activation and desensitization (2,5). Based on the Monod-Wyman-Changeux (MWC) model (6), it has been postulated that allosteric LGICs spontaneously exist in a reversible equilibrium between several quaternary structures: a resting state (R), an active open-channel state (A), and one or several high-affinity desensitized state(s) with a closed channel (D) (2,7). In this model, the effect of the ligand is described in terms of the affinity for the different states of the receptor; for example, agonist binding shifts the equilibrium to the A state and antagonist binding shifts the equilibrium to the R state.…”

mentioning

confidence: 99%

A gating mechanism of pentameric ligand-gated ion channels

Calimet

Simões

Changeux

et al. 2013

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

Self Cite

132

208

View full text Add to dashboard Cite

Pentameric ligand-gated ion channels (pLGICs) play a central role in intercellular communication in the nervous system and are involved in fundamental processes such as attention, learning, and memory. They are oligomeric protein assemblies that convert a chemical signal into an ion flux through the postsynaptic membrane, but the molecular mechanism of gating ions has remained elusive. Here, we present atomistic molecular dynamics simulations of the prokaryotic channels from Gloeobacter violaceus (GLIC) and Erwinia chrysanthemi (ELIC), whose crystal structures are thought to represent the active and the resting states of pLGICs, respectively, and of the eukaryotic glutamate-gated chloride channel from Caenorhabditis elegans (GluCl), whose openchannel structure was determined complexed with the positive allosteric modulator ivermectin. Structural observables extracted from the trajectories of GLIC and ELIC are used as progress variables to analyze the time evolution of GluCl, which was simulated in the absence of ivermectin starting from the structure with bound ivermectin. The trajectory of GluCl with ivermectin removed shows a sequence of structural events that couple agonist unbinding from the extracellular domain to ion-pore closing in the transmembrane domain. Based on these results, we propose a structural mechanism for the allosteric communication leading to deactivation/activation of the GluCl channel. This model of gating emphasizes the coupling between the quaternary twisting and the opening/closing of the ion pore and is likely to apply to other members of the pLGIC family.neurotransmitter receptors | chemo-electrical transduction | ion channel gating P entameric ligand-gated ion channels (pLGICs) mediate intercellular communication in the brain by converting a chemical signal, typically a local increase in the extracellular concentration of neurotransmitter, into an electrical signal, which is generated by an ion flux through the postsynaptic membrane (1). Understanding their function at an atomic level of detail is likely to be useful for the development of drug therapies against a range of disorders, including nicotine addiction, Alzheimer's disease, schizophrenia, and depression (2).pLGICs are oligomeric membrane proteins with a fivefold pseudosymmetry axis perpendicular to the membrane. Each subunit consists of an extracellular (EC) domain that contains the ligand-binding site and a transmembrane (TM) ion-pore domain. The agonist binding site is located at the boundary between subunits in the EC domain whereas the ion pore is formed by the transmembrane helices M2, which differentiate axial cationic and anionic channels (Fig. 1). An essential element of the mechanism is that these topologically distinct domains are allosterically coupled to each other (3, 4).Electrophysiology analysis of pLGICs first showed that the rapid delivery of agonist promotes fast opening of the channel whereas prolonged applications lead to a slow decrease of the response amplitude or "desensitization" (5). Several kineti...

show abstract

“…124 As a member of a superfamily of neurotransmitter ligand-gated ion channels, nAChRs have been investigated as therapeutic targets for medical treatment of central nervous system (CNS) disorders such as schizophrenia, nicotine addiction, and Alzheimer's disease. [125][126][127] However, the development of novel and potent ligands for specific receptor subtypes using classical drug discovery approaches has been difficult because of the nAChR membrane disposition, receptor subtypes diversity, and the dynamic nature of the binding site. Grimster et al turned their attention to the in situ click chemistry approach with the acetylcholine binding protein (AChBP) as a structural surrogate for nAChRs.…”

Section: In Situ Click Chemistry Experiments With Acetylcholine Bimentioning

confidence: 99%

The Lock is the Key: Development of Novel Drugs through Receptor Based Combinatorial Chemistry

Maraković

Šinko

2017

ACSi

View full text Add to dashboard Cite

Modern drug discovery is mainly based on the de novo synthesis of a large number of compounds with a diversity of chemical functionalities. Though the introduction of combinatorial chemistry enabled the preparation of large libraries of compounds from so-called building blocks, the problem of successfully identifying leads remains. The introduction of a dynamic combinatorial chemistry method served as a step forward due to the involvement of biological macromolecular targets (receptors) in the synthesis of high affinity products. The major breakthrough was a synthetic method in which building blocks are irreversibly combined due to the presence of a receptor. Here we present various receptor-based combinatorial chemistry approaches. Huisgen's cycloaddition (1,3-dipolar cycloaddition of azides and alkynes) forms stabile 1,2,3-triazoles with very high receptor affinity that can reach femtomolar levels, as the case with acetylcholinesterase inhibitors shows. Huisgen's cycloaddition can be applied to various receptors including acetylcholinesterase, acetylcholine binding protein, carbonic anhydrase-II, serine/threonine-protein kinase and minor groove of DNA.

show abstract

The nicotinic acetylcholine receptor: From molecular biology to cognition

Cited by 32 publications

References 16 publications

Dose–Response Analysis When There Is a Correlation between Affinity and Efficacy

Dose–Response Analysis When There Is a Correlation between Affinity and Efficacy

A gating mechanism of pentameric ligand-gated ion channels

The Lock is the Key: Development of Novel Drugs through Receptor Based Combinatorial Chemistry

Contact Info

Product

Resources

About