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Molecular investigations on the nicotinic acetylcholine receptor

Conformational mapping and dynamic exploration using photoaffinity labeling

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Abstract

The nicotinic acetylcholine receptor (nAChR) is a well-understood member of the ligand-gated ion channels superfamily. The members of this signaling proteins group, including 5HT3, GABAA, glycine, and ionotropic glutamate receptors, are thought to share common secondary, tertiary, and quaternary structures on the basis of a very high degree of sequence similarity. Despite the absence of X-ray crystallographic data, considerable progress on structural analysis of nAChR was achieved from biochemical, mutational, and electron microscopy data allowing the emergence of a three-dimensional image. Photoaffinity labeling and site-directed mutagenesis gave information on the tertiary structure with respect to the agonist/antagonist binding sites, the ion channel, and its selectivity filter.

nAChR is an allosterical protein that undergoes interconversion among several conformational states. Time-resolved photolabeling was used in an attempt to elucidate the structural changes that occur in nAChR on neurotransmitter activation. Tertiary and quaternary rearrangements were found in the cholinergic binding pocket and in the channel lumen, but the structural determinant and the functional link between the binding of agonist and the channel gating remain unknown. Time-resolved photolabeling of the functional activated A state using photosensitive agonists might help in understanding the dynamic process leading to the interconversion of the different states.

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Abbreviations

nAChR:

nicotinic acetylcholine receptor

ACh:

acetylcholine

NCB:

noncompetitive channel blocker

[3H]MBTA:

N-(4-maleimido)benzyltrimethylammonium iodide

[3H]DDF:

[3H]p-(N,N-dimethylamino) benzenediazonium fluoroborate

[3H]CPZ:

[3H]chloropromazine

[3H]TPMP:

[3H]triphenylmethylphosphonium cation

[125I]TID:

3-trifluoromethyl-3-(-m-[125I]iodophenyl)diazirine

[3H]QA:

[3H]quinacrine azide

[3H]DAF:

2-[3H]diazofluorene

[3H]DCTA:

[3H]diazocyclohexadienoylpropyl, trimethyammonium

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  1. Laboratoire de Chimie Bio-Organique, UMR 7514 CNRS, Faculté de Pharmacie-Université Louis Pasteur, 74 Route du Rhin, BP 24, 67401, Illkirch Cedex, France

    Florence Kotzyba-Hibert, Thomas Grutter & Maurice Goeldner

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  1. Florence Kotzyba-Hibert
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Kotzyba-Hibert, F., Grutter, T. & Goeldner, M. Molecular investigations on the nicotinic acetylcholine receptor. Mol Neurobiol 20, 45–59 (1999). https://doi.org/10.1007/BF02741364

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