Structure and function meet at the nicotinic acetylcholine receptor-lipid interface

Abstract: The nicotinic acetylcholine receptor (nAChR) is a transmembrane protein that mediates fast intercellular communication in response to the endogenous neurotransmitter acetylcholine. It is the best characterized and archetypal molecule in the superfamily of pentameric ligand-gated ion chan...

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Autor principal: Barrantes, Francisco José
Formato: Artículo
Lenguaje:Inglés
Publicado: Elsevier 2023
Materias:
RECEPTOR NICOTINICO DE ACETILCOLINA
COLESTEROL
LIPIDOS PROTEICOS VECINALES
DOMINIOS TRANSMEMBRANA
INTERACCIONES LIPIDO-RECEPTOR
Acceso en línea:https://repositorio.uca.edu.ar/handle/123456789/16473
Aporte de:
Repositorio Institucional de la Universidad Católica Argentina (UCA) de Universidad Católica Argentina
id I33-R139-123456789-16473
record_format dspace
spelling I33-R139-123456789-164732023-11-23T17:49:36Z Structure and function meet at the nicotinic acetylcholine receptor-lipid interface Barrantes, Francisco José RECEPTOR NICOTINICO DE ACETILCOLINA COLESTEROL LIPIDOS PROTEICOS VECINALES DOMINIOS TRANSMEMBRANA INTERACCIONES LIPIDO-RECEPTOR Abstract: The nicotinic acetylcholine receptor (nAChR) is a transmembrane protein that mediates fast intercellular communication in response to the endogenous neurotransmitter acetylcholine. It is the best characterized and archetypal molecule in the superfamily of pentameric ligand-gated ion channels (pLGICs). As a typical transmembrane macromolecule, it interacts extensively with its vicinal lipid microenvironment. Experimental evidence provides a wealth of information on receptor-lipid crosstalk: the nAChR exerts influence on its immediate membrane environment and conversely, the lipid moiety modulates ligand binding, affinity state transitions and gating of ion translocation functions of the receptor protein. Recent cryogenic electron microscopy (cryo-EM) studies have unveiled the occurrence of sites for phospholipids and cholesterol on the lipid-exposed regions of neuronal and electroplax nAChRs, confirming early spectroscopic and affinity labeling studies demonstrating the close contact of lipid molecules with the receptor transmembrane segments. This new data provides structural support to the postulated “lipid sensor” ability displayed by the outer ring of M4 transmembrane domains and their modulatory role on nAChR function, as we postulated a decade ago. Borrowing from the best characterized nAChR, the electroplax (muscle-type) receptor, and exploiting new structural information on the neuronal nAChR, it is now possible to achieve an improved depiction of these sites. In combination with site-directed mutagenesis, single-channel electrophysiology, and molecular dynamics studies, the new structural information delivers a more comprehensive portrayal of these lipid-sensitive loci, providing mechanistic explanations for their ability to modulate nAChR properties and raising the possibility of targetting them in disease. 2023-06-06T10:38:24Z 2023-06-06T10:38:24Z 2023 Artículo Barrantes, F. J. Structure and function meet at the nicotinic acetylcholine receptor-lipid interface [en línea]. Pharmacological Research. 2023 (190). doi: 10.1016/j.phrs.2023.106729. Disponible en: https://repositorio.uca.edu.ar/handle/123456789/16473 1096-1186 (online) https://repositorio.uca.edu.ar/handle/123456789/16473 10.1016/j.phrs.2023.106729 36931540 eng Acceso abierto http://creativecommons.org/licenses/by-nc-sa/4.0/ application/pdf Elsevier Pharmacological Research Vol.190, 2023
institution Universidad Católica Argentina
institution_str I-33
repository_str R-139
collection Repositorio Institucional de la Universidad Católica Argentina (UCA)
language Inglés
topic RECEPTOR NICOTINICO DE ACETILCOLINA
COLESTEROL
LIPIDOS PROTEICOS VECINALES
DOMINIOS TRANSMEMBRANA
INTERACCIONES LIPIDO-RECEPTOR
spellingShingle RECEPTOR NICOTINICO DE ACETILCOLINA
COLESTEROL
LIPIDOS PROTEICOS VECINALES
DOMINIOS TRANSMEMBRANA
INTERACCIONES LIPIDO-RECEPTOR
Barrantes, Francisco José
Structure and function meet at the nicotinic acetylcholine receptor-lipid interface
topic_facet RECEPTOR NICOTINICO DE ACETILCOLINA
COLESTEROL
LIPIDOS PROTEICOS VECINALES
DOMINIOS TRANSMEMBRANA
INTERACCIONES LIPIDO-RECEPTOR
description Abstract: The nicotinic acetylcholine receptor (nAChR) is a transmembrane protein that mediates fast intercellular communication in response to the endogenous neurotransmitter acetylcholine. It is the best characterized and archetypal molecule in the superfamily of pentameric ligand-gated ion channels (pLGICs). As a typical transmembrane macromolecule, it interacts extensively with its vicinal lipid microenvironment. Experimental evidence provides a wealth of information on receptor-lipid crosstalk: the nAChR exerts influence on its immediate membrane environment and conversely, the lipid moiety modulates ligand binding, affinity state transitions and gating of ion translocation functions of the receptor protein. Recent cryogenic electron microscopy (cryo-EM) studies have unveiled the occurrence of sites for phospholipids and cholesterol on the lipid-exposed regions of neuronal and electroplax nAChRs, confirming early spectroscopic and affinity labeling studies demonstrating the close contact of lipid molecules with the receptor transmembrane segments. This new data provides structural support to the postulated “lipid sensor” ability displayed by the outer ring of M4 transmembrane domains and their modulatory role on nAChR function, as we postulated a decade ago. Borrowing from the best characterized nAChR, the electroplax (muscle-type) receptor, and exploiting new structural information on the neuronal nAChR, it is now possible to achieve an improved depiction of these sites. In combination with site-directed mutagenesis, single-channel electrophysiology, and molecular dynamics studies, the new structural information delivers a more comprehensive portrayal of these lipid-sensitive loci, providing mechanistic explanations for their ability to modulate nAChR properties and raising the possibility of targetting them in disease.
format Artículo
author Barrantes, Francisco José
author_facet Barrantes, Francisco José
author_sort Barrantes, Francisco José
title Structure and function meet at the nicotinic acetylcholine receptor-lipid interface
title_short Structure and function meet at the nicotinic acetylcholine receptor-lipid interface
title_full Structure and function meet at the nicotinic acetylcholine receptor-lipid interface
title_fullStr Structure and function meet at the nicotinic acetylcholine receptor-lipid interface
title_full_unstemmed Structure and function meet at the nicotinic acetylcholine receptor-lipid interface
title_sort structure and function meet at the nicotinic acetylcholine receptor-lipid interface
publisher Elsevier
publishDate 2023
url https://repositorio.uca.edu.ar/handle/123456789/16473
work_keys_str_mv AT barrantesfranciscojose structureandfunctionmeetatthenicotinicacetylcholinereceptorlipidinterface
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