Characterization of scorpion peptide toxins that target voltage-gated potassium channels

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dc.contributor.advisorPanyi, György
dc.contributor.authorShakeel, Kashmala
dc.contributor.departmentMolekuláris orvostudomány doktori iskolahu
dc.contributor.submitterdepÁltalános Orvostudományi Kar::Biofizikai és Sejtbiológiai Intézet::Biofizikai Tanszék
dc.date.accessioned2025-07-18T12:03:53Z
dc.date.available2025-07-18T12:03:53Z
dc.date.defended2025-08-29
dc.date.issued2025
dc.description.abstractThe Kv1.2 ion channels play a vital role in the regulation of membrane potential and excitability of neurons and are widely distributed in CNS. In 2016, Kv1.2 related GOF mutations and their role in the progression of epileptic encephalopathy (EE) were described. It has been experimentally verified that the inhibition of the Kv1.2 current can be a potential approach to cure EE. The aim of this research was to identify and characterize a potent and selective inhibitor of Kv1.2 ion channel from the venom of scorpions. With the help of our collaborators, we isolated seven new peptides (CboK1-CboK7, 32-39 amino acid residues) from venom of C. bonito, two peptides from the venom of C. villegasi (Cvill6 and Cvill7, 38 and 39 amino acid residues) and a synthetic peptide, sCm39, which was identified from the venom of a known scorpion C. margaritatus. Electrophysiological characterization of seven peptides showed that among all except CboK1 all six peptides inhibit Kv1.2 with high affinity (Kd values between 24-763 pM) and have reasonable selectivity over Kv1.3 (Kd values between 20.4-171 nM). Of these seven, CboK7 emerged as a high-affinity and selective blocker of Kv1.2, having 850-fold and 6000-fold selectivity over Kv1.3 and Kv1.1. Pharmacological analysis of Cvill peptides shows that Cvill6 has moderate affinity for Kv1.2 (Kd = 3.9 nM) whereas Cvill7 possesses high Kv1.2 affinity (Kd = 16 pM). Cvill6 has 215-fold and 59-fold selectivity over Kv1.3 and KCa3.1, respectively. In contrast Cvill7 has high selectivity for Kv1.2 over Kv1.3 and KCa3.1 (450-fold and 33000-fold, respectively). Binding kinetics analysis suggests that Cvill6 and Cvill7 follow the binding pattern of classical pore blockers. sCm39 inhibited Kv1.2 currents with Kd value of 65 nM and does not show any effect on Kv1.1 and Kv1.3 at 1 at 1 µM. The investigation for the mechanism of block and binding kinetics revealed that Cm39 binds to the pore of the Kv1.2 ion channel thus it is not a gating-modifier. In summary, this dissertation presents the electrophysiological characterization of ten peptide toxins, among which two CboK7 and Cvill7 emerged as potent, high-affinity blockers of the Kv1.2 ion channel. These findings lay the groundwork for identifying key amino acid residues critical for high-affinity Kv1.2 blockade. Moreover, they provide a valuable foundation for the potential therapeutic application of Kv1.2-targeting peptides in the treatment of epileptic encephalopathy (EE) and other related neurological disorders.
dc.format.extent87
dc.identifier.urihttps://hdl.handle.net/2437/395842
dc.language.isoen
dc.subjectVoltage-gated potassium channel
dc.subjectKv1.2
dc.subjectKv1.2-related gain of function mutations
dc.subjectScorpion toxins
dc.subjectCboK toxins
dc.subjectCvill toxins
dc.subjectsCm39
dc.subjectPatch-clamp electrophysiology
dc.subjectIon channel pharmacology
dc.subject.disciplineElméleti orvostudományokhu
dc.subject.sciencefieldOrvostudományokhu
dc.titleCharacterization of scorpion peptide toxins that target voltage-gated potassium channels
dc.title.translatedCharacterization of scorpion peptide toxins that target voltage-gated potassium channels
dc.typePhD, doktori értekezéshu
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