Antibody-induced crosslinking and cholesterol-sensitive, anomalous diffusion of nicotinic acetylcholine receptors

Abstract: Synaptic strength depends on the number of cell-surface neurotransmitter receptors in dynamic equilibrium with intracellular pools. Dysregulation of this homeostatic balance occurs, for example in myasthenia gravis, an autoimmune disease characterized by a decrease in the number of postsyn...

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Autores principales: Mosqueira, Alejo, Camino, Pablo A., Barrantes, Francisco José
Formato: Artículo
Lenguaje:Inglés
Publicado: Wiley 2022
Materias:
MIASTENIA GRAVIS
ANTICUERPOS MONOCLONALES
COLESTEROL
Acceso en línea:https://repositorio.uca.edu.ar/handle/123456789/14228
Aporte de:
Repositorio Institucional de la Universidad Católica Argentina (UCA) de Universidad Católica Argentina
id I33-R139-123456789-14228
record_format dspace
institution Universidad Católica Argentina
institution_str I-33
repository_str R-139
collection Repositorio Institucional de la Universidad Católica Argentina (UCA)
language Inglés
topic MIASTENIA GRAVIS
ANTICUERPOS MONOCLONALES
COLESTEROL
spellingShingle MIASTENIA GRAVIS
ANTICUERPOS MONOCLONALES
COLESTEROL
Mosqueira, Alejo
Camino, Pablo A.
Barrantes, Francisco José
Antibody-induced crosslinking and cholesterol-sensitive, anomalous diffusion of nicotinic acetylcholine receptors
topic_facet MIASTENIA GRAVIS
ANTICUERPOS MONOCLONALES
COLESTEROL
description Abstract: Synaptic strength depends on the number of cell-surface neurotransmitter receptors in dynamic equilibrium with intracellular pools. Dysregulation of this homeostatic balance occurs, for example in myasthenia gravis, an autoimmune disease characterized by a decrease in the number of postsynaptic nicotinic acetylcholine receptors (nAChRs). Monoclonal antibody mAb35 mimics this effect. Here we use STORM nanoscopy to characterize the individual and ensemble dynamics of monoclonal antibody-crosslinked receptors in the clonal cell line CHO-K1/A5, which robustly expresses adult muscle-type nAChRs. Antibody labeling of live cells results in 80% receptor immobilization. The remaining mobile fraction exhibits a heterogeneous combination of Brownian and anomalous diffusion. Single-molecule trajectories exhibit a two-state switching behavior between free Brownian walks and anticorrelated walks within confinement areas. The latter act as permeable fences (~34 nm radius, ~400 ms lifetime). Dynamic clustering, trapping, and immobilization also occur in larger nanocluster zones (120-180 nm radius) with longer lifetimes (11 ± 1 s), in a strongly cholesterol-sensitive manner. Cholesterol depletion increases the size of the clustering phenomenon; cholesterol enrichment has the opposite effect. The disclosed high proportion of monoclonal antibody-crosslinked immobile receptors, together with their anomalous, cholesterol-sensitive diffusion and clustering, provides new insights into the antibody-enhanced antigenic modulation that leads to physiopathological internalization and degradation of receptors in myasthenia.
format Artículo
author Mosqueira, Alejo
Camino, Pablo A.
Barrantes, Francisco José
author_facet Mosqueira, Alejo
Camino, Pablo A.
Barrantes, Francisco José
author_sort Mosqueira, Alejo
title Antibody-induced crosslinking and cholesterol-sensitive, anomalous diffusion of nicotinic acetylcholine receptors
title_short Antibody-induced crosslinking and cholesterol-sensitive, anomalous diffusion of nicotinic acetylcholine receptors
title_full Antibody-induced crosslinking and cholesterol-sensitive, anomalous diffusion of nicotinic acetylcholine receptors
title_fullStr Antibody-induced crosslinking and cholesterol-sensitive, anomalous diffusion of nicotinic acetylcholine receptors
title_full_unstemmed Antibody-induced crosslinking and cholesterol-sensitive, anomalous diffusion of nicotinic acetylcholine receptors
title_sort antibody-induced crosslinking and cholesterol-sensitive, anomalous diffusion of nicotinic acetylcholine receptors
publisher Wiley
publishDate 2022
url https://repositorio.uca.edu.ar/handle/123456789/14228
work_keys_str_mv AT mosqueiraalejo antibodyinducedcrosslinkingandcholesterolsensitiveanomalousdiffusionofnicotinicacetylcholinereceptors
AT caminopabloa antibodyinducedcrosslinkingandcholesterolsensitiveanomalousdiffusionofnicotinicacetylcholinereceptors
AT barrantesfranciscojose antibodyinducedcrosslinkingandcholesterolsensitiveanomalousdiffusionofnicotinicacetylcholinereceptors
bdutipo_str Repositorios
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