CANNABIDIOL INHIBITS BK CHANNELS

MONAT, J; GONZÁLEZ ALTIERI, L; ENRIQUE, N; SEDÁN, D; ANDRINOLO, D; MILESI, V; MARTÍN, P

Mar del Plata

Congreso; Reunión anual de Sociedades de Biociencias; 2023

SAIC

Cannabidiol (CBD), one of the main Cannabis sativa bioactive substances, is receiving attention with the speculation that it can be useful in a wide-range of conditions. In particular, CBD is approved for the treatment of major epileptic syndromes. In the central nervous system, several CBD targets have been proposed, including endocannabinoid receptors, and different types of ion channels such as TRPV1, VDAC1, voltage-operated Na+, and T-type Ca2+ channels, among others. The large conductance voltage- and calcium-activated K+ (BK) channel is involved in fast action potential repolarization, and regulates its shape and duration. BK channel inhibition has been proposed as an anticonvulsant mechanism. Here, we explore the effect of CBD on the BK channel heterologously expressed in HEK cells. Using the patch clamp technique in the inside-out configuration we observed that CBD inhibits BK channel currents in a concentration-dependent manner showing an IC50 of 282,9 nM (pIC50: 6.55 ± 0.06; Hill slope: 0.98 ± 0.12, n=5-9). The direct inhibition of the BK channel by 1 µM CBD results in a half-decrease in the maximal conductance (Gmax: 0.52 ± 0.06, n=8) and a shift in activation curves to more depolarized voltages (ΔV1/2: 22.9 ± 4.4, n=8). Moreover, CBD significantly delays BK activation kinetic, suggesting a closed channel stabilization (for 1 µM CBD, at +100 mV: τCBD= 15.5 ± 2.1 ms vs. τcontrol= 5.5 ± 1.3 ms n= 5, p