The voltage-gated sodium channel pore exhibits conformational flexibility during slow inactivation.
J Gen Physiol
; 150(9): 1333-1347, 2018 09 03.
Article
en En
| MEDLINE
| ID: mdl-30082431
ABSTRACT
Slow inactivation in voltage-gated sodium channels (NaVs) directly regulates the excitability of neurons, cardiac myocytes, and skeletal muscles. Although NaV slow inactivation appears to be conserved across phylogenies-from bacteria to humans-the structural basis for this mechanism remains unclear. Here, using site-directed labeling and EPR spectroscopic measurements of membrane-reconstituted prokaryotic NaV homologues, we characterize the conformational dynamics of the selectivity filter region in the conductive and slow-inactivated states to determine the molecular events underlying NaV gating. Our findings reveal profound conformational flexibility of the pore in the slow-inactivated state. We find that the P1 and P2 pore helices undergo opposing movements with respect to the pore axis. These movements result in changes in volume of both the central and intersubunit cavities, which form pathways for lipophilic drugs that modulate slow inactivation. Our findings therefore provide novel insight into the molecular basis for state-dependent effects of lipophilic drugs on channel function.
Texto completo:
1
Colección:
01-internacional
Base de datos:
MEDLINE
Asunto principal:
Canales de Sodio Activados por Voltaje
Límite:
Humans
Idioma:
En
Revista:
J Gen Physiol
Año:
2018
Tipo del documento:
Article