Scorpion toxin peptide BMK86-P1 achieves mutation-reversible inhibition of KCNA2 at the cost of reduced efficacy in heteromers and murine neurons
- 1Department Neurology and Epileptology, Hertie Institute for Clinical Brain Research, University of Tübingen
- 2Institute of Clinical Anatomy and Cell Analysis, University of Tübingen
Abstract
The discovery of distinctive function-phenotype relationships in monogenetic channelopathies has turned out to be critical for the development of precision medicine approaches. However, the most accurate prediction of clinical phenotypes depends on neuronal function, where existing models lack tools to isolate currents of individual voltage-gated potassium channel subunits and to differentiate variant effects in complex systems. Ideally, one should be able to overexpress subunit variants with an additional mutation that would confer resistance against the tool used to isolate the variant effect. Therefore, we solid-phase synthesized the K V 1.2 specific scorpion toxin peptide BMK86-P1 and oxidized it with modest efficacy. In mammalian cells this BMK86-P1 selectively inhibited K V 1.2 homomers, but not heteromers with K V 1.1. Critically, the KCNA2 p. Val381Tyr mutation, which reverses BMK86-P1’s selective inhibition of K V 1.2, also altered the activation of K V 1.2 homomers to resemble those of K V 1.1. In addition, in murine neurons, BMK86-P1 did not alter passive membrane properties, single action potential properties, or action potential firing. Surprisingly, it induced only minimal changes in spontaneous excitatory postsynaptic currents. In summary, this K V 1.2 subunit selective toxin peptide primarily affects homomeric channels, while only weakly inhibiting K V 1.2/K V 1.1 heteromeric channels and consequently preventing any meaningful impact on neuronal function. This highlights the limitations of peptide synthesis together with the need for testing specific compounds on complex systems.
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BibTeX
@article{brand2026scorpion,
title = {{Scorpion toxin peptide BMK86-P1 achieves mutation-reversible inhibition of KCNA2 at the cost of reduced efficacy in heteromers and murine neurons}},
author = {Elisabeth M. M. Brand and Lorenz Over and Hubert Kalbacher and Remy Lambert and Stefano Iavarone and Hang Lyu and Ulrike B. S. Hedrich and Peter Müller-Wöhrstein},
journal = {Frontiers in Pharmacology},
year = {2026},
month = oct,
doi = {10.3389/fphar.2026.1949571},
url = {https://www.frontiersin.org/articles/10.3389/fphar.2026.1949571/full},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - Scorpion toxin peptide BMK86-P1 achieves mutation-reversible inhibition of KCNA2 at the cost of reduced efficacy in heteromers and murine neurons
AU - Elisabeth M. M. Brand
AU - Lorenz Over
AU - Hubert Kalbacher
AU - Remy Lambert
AU - Stefano Iavarone
AU - Hang Lyu
AU - Ulrike B. S. Hedrich
AU - Peter Müller-Wöhrstein
PY - 2026
DA - 2026/10/13
JO - Frontiers in Pharmacology
DO - 10.3389/fphar.2026.1949571
UR - https://www.frontiersin.org/articles/10.3389/fphar.2026.1949571/full
AB - The discovery of distinctive function-phenotype relationships in monogenetic channelopathies has turned out to be critical for the development of precision medicine approaches. However, the most accurate prediction of clinical phenotypes depends on neuronal function, where existing models lack tools to isolate currents of individual voltage-gated potassium channel subunits and to differentiate variant effects in complex systems. Ideally, one should be able to overexpress subunit variants with an additional mutation that would confer resistance against the tool used to isolate the variant effect. Therefore, we solid-phase synthesized the K V 1.2 specific scorpion toxin peptide BMK86-P1 and oxidized it with modest efficacy. In mammalian cells this BMK86-P1 selectively inhibited K V 1.2 homomers, but not heteromers with K V 1.1. Critically, the KCNA2 p. Val381Tyr mutation, which reverses BMK86-P1’s selective inhibition of K V 1.2, also altered the activation of K V 1.2 homomers to resemble those of K V 1.1. In addition, in murine neurons, BMK86-P1 did not alter passive membrane properties, single action potential properties, or action potential firing. Surprisingly, it induced only minimal changes in spontaneous excitatory postsynaptic currents. In summary, this K V 1.2 subunit selective toxin peptide primarily affects homomeric channels, while only weakly inhibiting K V 1.2/K V 1.1 heteromeric channels and consequently preventing any meaningful impact on neuronal function. This highlights the limitations of peptide synthesis together with the need for testing specific compounds on complex systems.
SN - 1663-9812
ER -