Scorpion toxin peptide BMK86-P1 achieves mutation-reversible inhibition of KCNA2 at the cost of reduced efficacy in heteromers and murine neurons

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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.