A Non-covalent Ligand Reveals Biased Agonism of the TRPA1 Ion Channel.
Neuron
; 109(2): 273-284.e4, 2021 01 20.
Article
en En
| MEDLINE
| ID: mdl-33152265
ABSTRACT
The TRPA1 ion channel is activated by electrophilic compounds through the covalent modification of intracellular cysteine residues. How non-covalent agonists activate the channel and whether covalent and non-covalent agonists elicit the same physiological responses are not understood. Here, we report the discovery of a non-covalent agonist, GNE551, and determine a cryo-EM structure of the TRPA1-GNE551 complex, revealing a distinct binding pocket and ligand-interaction mechanism. Unlike the covalent agonist allyl isothiocyanate, which elicits channel desensitization, tachyphylaxis, and transient pain, GNE551 activates TRPA1 into a distinct conducting state without desensitization and induces persistent pain. Furthermore, GNE551-evoked pain is relatively insensitive to antagonist treatment. Thus, we demonstrate the biased agonism of TRPA1, a finding that has important implications for the discovery of effective drugs tailored to different disease etiologies.
Palabras clave
Texto completo:
1
Colección:
01-internacional
Banco de datos:
MEDLINE
Asunto principal:
Dimensión del Dolor
/
Canal Catiónico TRPA1
Límite:
Animals
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Female
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Humans
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Male
Idioma:
En
Revista:
Neuron
Asunto de la revista:
NEUROLOGIA
Año:
2021
Tipo del documento:
Article
País de afiliación:
Estados Unidos