Kainate receptor channel opening and gating mechanism.
Nature
; 630(8017): 762-768, 2024 Jun.
Article
em En
| MEDLINE
| ID: mdl-38778115
ABSTRACT
Kainate receptors, a subclass of ionotropic glutamate receptors, are tetrameric ligand-gated ion channels that mediate excitatory neurotransmission1-4. Kainate receptors modulate neuronal circuits and synaptic plasticity during the development and function of the central nervous system and are implicated in various neurological and psychiatric diseases, including epilepsy, depression, schizophrenia, anxiety and autism5-11. Although structures of kainate receptor domains and subunit assemblies are available12-18, the mechanism of kainate receptor gating remains poorly understood. Here we present cryo-electron microscopy structures of the kainate receptor GluK2 in the presence of the agonist glutamate and the positive allosteric modulators lectin concanavalin A and BPAM344. Concanavalin A and BPAM344 inhibit kainate receptor desensitization and prolong activation by acting as a spacer between the amino-terminal and ligand-binding domains and a stabilizer of the ligand-binding domain dimer interface, respectively. Channel opening involves the kinking of all four pore-forming M3 helices. Our structures reveal the molecular basis of kainate receptor gating, which could guide the development of drugs for treatment of neurological disorders.
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Modelos Moleculares
/
Ativação do Canal Iônico
/
Receptores de Ácido Caínico
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Ácido Glutâmico
/
Concanavalina A
/
Microscopia Crioeletrônica
/
Domínios Proteicos
/
Receptor de GluK2 Cainato
Limite:
Animals
/
Humans
Idioma:
En
Revista:
Nature
/
Nature (Lond.)
/
Nature (London)
Ano de publicação:
2024
Tipo de documento:
Article
País de afiliação:
Estados Unidos
País de publicação:
Reino Unido