A missense mutation converts the Na+,K+-ATPase into an ion channel and causes therapy-resistant epilepsy.
J Biol Chem
; 297(6): 101355, 2021 12.
Article
en En
| MEDLINE
| ID: mdl-34717959
ABSTRACT
The ion pump Na+,K+-ATPase is a critical determinant of neuronal excitability; however, its role in the etiology of diseases of the central nervous system (CNS) is largely unknown. We describe here the molecular phenotype of a Trp931Arg mutation of the Na+,K+-ATPase catalytic α1 subunit in an infant diagnosed with therapy-resistant lethal epilepsy. In addition to the pathological CNS phenotype, we also detected renal wasting of Mg2+. We found that membrane expression of the mutant α1 protein was low, and ion pumping activity was lost. Arginine insertion into membrane proteins can generate water-filled pores in the plasma membrane, and our molecular dynamic (MD) simulations of the principle states of Na+,K+-ATPase transport demonstrated massive water inflow into mutant α1 and destabilization of the ion-binding sites. MD simulations also indicated that a water pathway was created between the mutant arginine residue and the cytoplasm, and analysis of oocytes expressing mutant α1 detected a nonspecific cation current. Finally, neurons expressing mutant α1 were observed to be depolarized compared with neurons expressing wild-type protein, compatible with a lowered threshold for epileptic seizures. The results imply that Na+,K+-ATPase should be considered a neuronal locus minoris resistentia in diseases associated with epilepsy and with loss of plasma membrane integrity.
Palabras clave
Texto completo:
1
Bases de datos:
MEDLINE
Asunto principal:
ATPasa Intercambiadora de Sodio-Potasio
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Mutación Missense
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Epilepsia
Tipo de estudio:
Etiology_studies
Límite:
Animals
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Humans
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Infant
Idioma:
En
Revista:
J Biol Chem
Año:
2021
Tipo del documento:
Article
País de afiliación:
Suecia