Subtype-specific modulation of human Kv7 channels by the anticonvulsant cannabidiol through a lipid-exposed pore-domain site

Br J Pharmacol. 2023 Jun 28. doi: 10.1111/bph.16183. Online ahead of print.

ABSTRACT

BACKGROUND AND PURPOSE: Cannabidiol (CBD) is used clinically as an anticonvulsant. However, its precise mechanism of action has remained elusive. CBD was recently demonstrated to enhance the activity of the neuronal KV 7.2/7.3 channel, which may be one important contributor to CBD’s anticonvulsant effect. Curiously, CBD inhibits the closely related cardiac KV 7.1/KCNE1 channel. However, whether and how CBD affects other KV 7 subtypes remains unstudied, and the CBD interaction sites mediating these diverse effects remain unknown.

EXPERIMENTAL APPROACH: Here, we used electrophysiology, molecular dynamics simulations, molecular docking, and site-directed mutagenesis to address these open questions.

KEY RESULTS: We found that CBD modulates the activity of all human KV 7 subtypes and that the effects are subtype-dependent. CBD enhanced the activity of KV 7.2-7.5 subtypes, seen as a V50 shift towards more negative voltages or increased maximum conductance. In contrast, CBD inhibited the KV 7.1 and KV 7.1/KCNE1 channels, seen as a V50 shift towards more positive voltages and reduced conductance. In KV 7.2 and KV 7.4, we propose a CBD interaction site at the subunit interface in the pore domain which overlaps with the interaction site of other compounds, notably the anticonvulsant retigabine. However, CBD relies on other residues for its effects than the conserved tryptophan that is critical for retigabine effects. We propose a similar, though not identical CBD site in KV 7.1, with a non-conserved phenylalanine being important.

CONCLUSIONS AND IMPLICATIONS: We identify novel targets of CBD, contributing to a better understanding of CBD’s clinical effects, and provide mechanistic insights into how CBD modulates different KV 7 subtypes.

PMID:37377025 | DOI:10.1111/bph.16183