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FASEB J ; 38(1): e23381, 2024 01.
Artigo em Inglês | MEDLINE | ID: mdl-38102952

RESUMO

Dysfunction of the human voltage-gated K+ channel Kv1.1 has been associated with epilepsy, multiple sclerosis, episodic ataxia, myokymia, and cardiorespiratory dysregulation. We report here that AETX-K, a sea anemone type I (SAK1) peptide toxin we isolated from a phage display library, blocks Kv1.1 with high affinity (Ki ~ 1.6 pM) and notable specificity, inhibiting other Kv channels we tested a million-fold less well. Nuclear magnetic resonance (NMR) was employed both to determine the three-dimensional structure of AETX-K, showing it to employ a classic SAK1 scaffold while exhibiting a unique electrostatic potential surface, and to visualize AETX-K bound to the Kv1.1 pore domain embedded in lipoprotein nanodiscs. Study of Kv1.1 in Xenopus oocytes with AETX-K and point variants using electrophysiology demonstrated the blocking mechanism to employ a toxin-channel configuration we have described before whereby AETX-K Lys23 , two positions away on the toxin interaction surface from the classical blocking residue, enters the pore deeply enough to interact with K+ ions traversing the pathway from the opposite side of the membrane. The mutant channel Kv1.1-L296 F is associated with pharmaco-resistant multifocal epilepsy in infants because it significantly increases K+ currents by facilitating opening and slowing closure of the channels. Consistent with the therapeutic potential of AETX-K for Kv1.1 gain-of-function-associated diseases, AETX-K at 4 pM decreased Kv1.1-L296 F currents to wild-type levels; further, populations of heteromeric channels formed by co-expression Kv1.1 and Kv1.2, as found in many neurons, showed a Ki of ~10 nM even though homomeric Kv1.2 channels were insensitive to the toxin (Ki > 2000 nM).


Assuntos
Epilepsia , Mutação com Ganho de Função , Humanos , Peptídeos/genética , Peptídeos/farmacologia , Epilepsia/genética , Bloqueadores dos Canais de Potássio/farmacologia
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