scholarly journals Molecular Determinants of Subtype-selective Efficacies of Cytisine and the Novel Compound NS3861 at Heteromeric Nicotinic Acetylcholine Receptors

2012 ◽  
Vol 288 (4) ◽  
pp. 2559-2570 ◽  
Author(s):  
Kasper Harpsøe ◽  
Helle Hald ◽  
Daniel B. Timmermann ◽  
Marianne L. Jensen ◽  
Tino Dyhring ◽  
...  
Keyword(s):  
Nicotinic Acetylcholine Receptors ◽  
Acetylcholine Receptors ◽  
The Novel ◽  
Nicotinic Acetylcholine ◽  
Molecular Determinants ◽  
Subtype Selective

scholarly journals Molecular Determinants for Competitive Inhibition of α4β2 Nicotinic Acetylcholine Receptors

2010 ◽  
Vol 78 (3) ◽  
pp. 366-375 ◽  
Author(s):  
Patricio Iturriaga-Vásquez ◽  
Annalisa Carbone ◽  
Olimpo García-Beltrán ◽  
Phil D. Livingstone ◽  
Philip C. Biggin ◽  
...  
Keyword(s):  
Nicotinic Acetylcholine Receptors ◽  
Acetylcholine Receptors ◽  
Competitive Inhibition ◽  
Nicotinic Acetylcholine ◽  
Molecular Determinants

5-Iodo-A-85380, an α4β2 Subtype-Selective Ligand for Nicotinic Acetylcholine Receptors

2000 ◽  
Vol 57 (3) ◽  
pp. 642-649 ◽  
Author(s):  
Alexey G. Mukhin ◽  
Daniela Gündisch ◽  
Andrew G. Horti ◽  
Andrei O. Koren ◽  
Gilles Tamagnan ◽  
...  
Keyword(s):  
Nicotinic Acetylcholine Receptors ◽  
Acetylcholine Receptors ◽  
Nicotinic Acetylcholine ◽  
Selective Ligand ◽  
Subtype Selective

scholarly journals High-Throughput Patch Clamp Screening in Human α6-Containing Nicotinic Acetylcholine Receptors

2017 ◽  
Vol 22 (6) ◽  
pp. 686-695 ◽  
Author(s):  
Lucas C. Armstrong ◽  
Glenn E. Kirsch ◽  
Nikolai B. Fedorov ◽  
Caiyun Wu ◽  
Yuri A. Kuryshev ◽  
...  
Keyword(s):  
Patch Clamp ◽  
Cell Line ◽  
Nicotinic Acetylcholine Receptors ◽  
Acetylcholine Receptors ◽  
Brain Regions ◽  
Tobacco Product ◽  
Tobacco Products ◽  
Nicotinic Acetylcholine ◽  
Automated Patch Clamp ◽  
Subtype Selective

Nicotine, the addictive component of tobacco products, is an agonist at nicotinic acetylcholine receptors (nAChRs) in the brain. The subtypes of nAChR are defined by their α- and β-subunit composition. The α6β2β3 nAChR subtype is expressed in terminals of dopaminergic neurons that project to the nucleus accumbens and striatum and modulate dopamine release in brain regions involved in nicotine addiction. Although subtype-dependent selectivity of nicotine is well documented, subtype-selective profiles of other tobacco product constituents are largely unknown and could be essential for understanding the addiction-related neurological effects of tobacco products. We describe the development and validation of a recombinant cell line expressing human α6/3β2β3V273S nAChR for screening and profiling assays in an automated patch clamp platform (IonWorks Barracuda). The cell line was pharmacologically characterized by subtype-selective and nonselective reference agonists, pore blockers, and competitive antagonists. Agonist and antagonist effects detected by the automated patch clamp approach were comparable to those obtained by conventional electrophysiological assays. A pilot screen of a library of Food and Drug Administration–approved drugs identified compounds, previously not known to modulate nAChRs, which selectively inhibited the α6/3β2β3V273S subtype. These assays provide new tools for screening and subtype-selective profiling of compounds that act at α6β2β3 nicotinic receptors.

scholarly journals An Inside Job: Molecular Determinants for Postsynaptic Localization of Nicotinic Acetylcholine Receptors

Molecules ◽  
2021 ◽  
Vol 26 (11) ◽  
pp. 3065
Author(s):  
Michael Ferns
Keyword(s):  
Nicotinic Acetylcholine Receptors ◽  
Acetylcholine Receptors ◽  
Adaptor Proteins ◽  
Scaffolding Proteins ◽  
Nicotinic Acetylcholine ◽  
Functional Studies ◽  
Molecular Determinants ◽  
Α3 Subunit ◽  
Cytoplasmic Loops ◽  
Intracellular Domains

Nicotinic acetylcholine receptors (nAChRs) mediate fast synaptic transmission at neuromuscular and autonomic ganglionic synapses in the peripheral nervous system. The postsynaptic localization of muscle ((α1)2β1γδ) and neuronal ((α3β4)2β4) nicotinic receptors at these synapses is mediated by interactions between the nAChR intracellular domains and cytoplasmic scaffolding proteins. Recent high resolution structures and functional studies provide new insights into the molecular determinants that mediate these interactions. Surprisingly, they reveal that the muscle nAChR binds 1–3 rapsyn scaffolding molecules, which dimerize and thereby form an interconnected lattice between receptors. Moreover, rapsyn binds two distinct sites on the nAChR subunit cytoplasmic loops; the MA-helix on one or more subunits and a motif specific to the β subunit. Binding at the latter site is regulated by agrin-induced phosphorylation of βY390, and increases the stoichiometry of rapsyn/AChR complexes. Similarly, the neuronal nAChR may be localized at ganglionic synapses by phosphorylation-dependent interactions with 14-3-3 adaptor proteins which bind specific motifs in each of the α3 subunit cytoplasmic loops. Thus, postsynaptic localization of nAChRs is mediated by regulated interactions with multiple scaffolding molecules, and the stoichiometry of these complexes likely helps regulate the number, density, and stability of receptors at the synapse.

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