Development of charybdotoxin Q18F variant as a selective peptide blocker of neuronal BK(α + ß4) channel for the treatment of epileptic seizures.
Protein Sci
; 31(12): e4506, 2022 12.
Article
em En
| MEDLINE
| ID: mdl-36369672
ABSTRACT
Epilepsy is the results from the imbalance between inhibition and excitation in neural circuits, which is mainly treated by some chemical drugs with side effects. Gain-of-function of BK channels or knockout of its ß4 subunit associates with spontaneous epilepsy. Currently, few reports were published about the efficacy of BK(α + ß4) channel modulators in epilepsy prevention. Charybdotoxin is a non-specific inhibitor of BK and other K+ channels. Here, by nuclear magnetic resonance (NMR) and other biochemical techniques, we found that charybdotoxin might interact with the extracellular loop of human ß4 subunit (i.e., hß4-loop) of BK(α + ß4) channel at a molar ratio 41 (hß4-loop vs. charybdotoxin). Charybdotoxin enhanced its ability to prevent K+ current of BK(α + ß4 H101Y) channel. The charybdotoxin Q18F variant selectively reduced the neuronal spiking frequency and increased interspike intervals of BK(α + ß4) channel by π-π stacking interactions between its residue Phe18 and residue His101 of hß4-loop. Moreover, intrahippocampal infusion of charybdotoxin Q18F variant significantly increased latency time of seizure, reduced seizure duration and seizure numbers on pentylenetetrazole-induced pre-sensitized rats, inhibited hippocampal hyperexcitability and c-Fos expression, and displayed neuroprotective effects on hippocampal neurons. These results implied that charybdotoxin Q18F variant could be potentially used for intractable epilepsy treatment by therapeutically targeting BK(α + ß4) channel.
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Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Charibdotoxina
/
Epilepsia
/
Canais de Potássio Ativados por Cálcio de Condutância Alta
Limite:
Animals
/
Humans
Idioma:
En
Revista:
Protein Sci
Assunto da revista:
BIOQUIMICA
Ano de publicação:
2022
Tipo de documento:
Article
País de afiliação:
China