Unconventional interactions of the TRPV4 ion channel with beta-adrenergic receptor ligands
Por:
Benitez-Angeles, Miguel, Juarez-Gonzalez, Emmanuel, Vergara-Jaque, Ariela, Llorente, Itzel, Rangel-Yescas, Gisela, Thebault, Stephanie C., Hiriart, Marcia, Islas, Leon D., Rosenbaum, Tamara
Publicada:
1 mar 2022
Resumen:
The transient receptor potential vanilloid 4 (TRPV4) ion channel is
present in different tissues including those of the airways. This
channel is activated in response to stimuli such as changes in
temperature, hypoosmotic conditions, mechanical stress, and chemicals
from plants, lipids, and others. TRPV4's overactivity and/ or
dysfunction has been associated with several diseases, such as skeletal
dysplasias, neuromuscular disorders, and lung patholo-gies such as
asthma and cardiogenic lung edema and COVID-19- related respiratory
malfunction. TRPV4 antagonists and blockers have been described;
nonetheless, the mechanisms involved in achieving inhibition of the
channel remain scarce, and the search for safe use of these molecules in
humans continues. Here, we show that the widely used bronchodilator
salbutamol and other ligands of beta-adrenergic receptors inhibit
TRPV4's activation. We also demonstrate that inhibition of TRPV4 by
salbutamol is achieved through interaction with two residues located in
the outer region of the pore and that salbutamol leads to channel
closing, consistent with an allosteric mechanism. Our study pro-vides
molecular insights into the mechanisms that regulate the activity of
this physiopathologically important ion channel.
Filiaciones:
Benitez-Angeles, Miguel:
Departamento de Neurociencia Cognitiva, Instituto de Fisiología Celular, Universidad Nacional Autónoma de México (UNAM), Mexico
Juarez-Gonzalez, Emmanuel:
Departamento de Neurociencia Cognitiva, Instituto de Fisiología Celular, Universidad Nacional Autónoma de México (UNAM), Mexico
Vergara-Jaque, Ariela:
Center for Bioinformatics, Simulation and Modeling, Faculty of Engineering, Universidad de Talca, Talca, Chile
Millennium Nucleus of Ion Channel-Associated DiseasesSantiago, Chile
Llorente, Itzel:
Departamento de Neurociencia Cognitiva, Instituto de Fisiología Celular, Universidad Nacional Autónoma de México (UNAM), Mexico
Rangel-Yescas, Gisela:
Departamento de Fisiología, Facultad de Medicina, UNAM, Mexico
Thebault, Stephanie C.:
Instituto de Neurobiología, UNAM, Campus UNAM-JuriquillaQuerétaro, Mexico
Hiriart, Marcia:
Departamento de Neurociencia Cognitiva, Instituto de Fisiología Celular, Universidad Nacional Autónoma de México (UNAM), Mexico
Islas, Leon D.:
Departamento de Fisiología, Facultad de Medicina, UNAM, Mexico
Rosenbaum, Tamara:
Departamento de Neurociencia Cognitiva, Instituto de Fisiología Celular, Universidad Nacional Autónoma de México (UNAM), Mexico
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