Research square · 2025
Effects of Emodepside on Single-Channel Properties of Onchocerca volvulus SLO-1A (BK) Potassium Channels.
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Njeshi Charity Nya, Choudhary Shivani, McHugh Mark Andrew, Kashyap Sudhanva Srinivas, Robertson Alan Patrick, Martin Richard John
Аннотация
BACKGROUND: Control of onchocerciasis (river blindness of humans due to infection with the filarial nematode, Onchocerca volvulus) remains a challenge because of the lack of effective adulticides and vaccines. Emodepside is a broad-spectrum veterinary anthelmintic that has been found to inhibit nematode muscle activity by activating their tetrameric SLO-1K channels. Emodepside has adulticidal activity and is being trialed for onchocerciasis treatment, but the molecular mode of action of emodepside is still being elucidated. Here we examine the single-channel currents of Ovo-SLO-1A, a SLO-1K splice variant from O. volvulus, and explore how emodepside modulates the dynamics of the opening of the channel.
METHODS: Ovo-SLO-1A was expressed in HEK 293 cells, and patch clamp electrophysiology techniques were used to record currents. Single-channel currents were recorded in a symmetrical 132 mM K+ solution to determine the main open-state channel conductance. Emodepside's effects were tested at 0.3 μM and 1.0 μM.
RESULTS: Ovo-SLO-1A had a main open-state conductance of 110 ± 3 pS and frequent flickering sub-conductance states. The presence of the flickering sub-conductance states suggests that there is limited cooperativity between the tetrameric channel subunits required for opening to the main open-state. Emodepside increased mean current amplitudes. Emodepside also increased open-burst times, and open probability. Verruculogen (1 μM) inhibited channel opening in the presence or absence of emodepside.
CONCLUSION: This study successfully expressed Ovo-SLO-1A in HEK 293 cells, measured the conductance of the main open-state and detected the presence of sub-conductance states, and flickering openings. The increased amplitudes of the single-channel currents, open-burst times and open probabilities provide insights into how emodepside increases Slo-1K currents and illustrate dynamic actions of emodepside on Ovo-SLO-1A.
METHODS: Ovo-SLO-1A was expressed in HEK 293 cells, and patch clamp electrophysiology techniques were used to record currents. Single-channel currents were recorded in a symmetrical 132 mM K+ solution to determine the main open-state channel conductance. Emodepside's effects were tested at 0.3 μM and 1.0 μM.
RESULTS: Ovo-SLO-1A had a main open-state conductance of 110 ± 3 pS and frequent flickering sub-conductance states. The presence of the flickering sub-conductance states suggests that there is limited cooperativity between the tetrameric channel subunits required for opening to the main open-state. Emodepside increased mean current amplitudes. Emodepside also increased open-burst times, and open probability. Verruculogen (1 μM) inhibited channel opening in the presence or absence of emodepside.
CONCLUSION: This study successfully expressed Ovo-SLO-1A in HEK 293 cells, measured the conductance of the main open-state and detected the presence of sub-conductance states, and flickering openings. The increased amplitudes of the single-channel currents, open-burst times and open probabilities provide insights into how emodepside increases Slo-1K currents and illustrate dynamic actions of emodepside on Ovo-SLO-1A.