CANNABIDIOL INHIBITS BK CHANNEL

JULIANA MONAT; LUCÍA GONZÁLEZ ALTIERI; NICOLÁS ENRIQUE; DANIELA SEDÁN; DARIO ANDRINOLO; VERÓNICA MILESI; PEDRO MARTÍN

Mar del Plata

Congreso; Reunión Anual de Sociedades de Biociencias; 2023

So

cannabidiol (CBD), one of the main Cannabis sativa bioactive sub-stances, is receiving attention with the speculation that it can be use-ful in a wide-range of conditions. In particular, CBD is approved forthe treatment of major epileptic syndromes. In the central nervoussystem, several CBD targets have been proposed, including endo-cannabinoid receptors, and different types of ion channels such asTRPV1, VDAC1, voltage-operated Na+, and T-type Ca2+ channels,among others. The large conductance voltage- and calcium-activat-ed K+ (BK) channel is involved in fast action potential repolariza-tion, and regulates its shape and duration. BK channel inhibition hasbeen proposed as an anticonvulsant mechanism. Here, we explorethe effect of CBD on the BK channel heterologously expressed inHEK cells. Using the patch clamp technique in the inside-out con-figuration we observed that CBD inhibits BK channel currents ina 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 inhi-bition of the BK channel by 1 μM CBD results in a half-decrease inthe maximal conductance (Gmax: 0.52 ± 0.06, n=8) and a shift in acti-vation curves to more depolarized voltages (ΔV1/2: 22.9 ± 4.4, n=8).Moreover, CBD significantly delays BK activation kinetic, suggestinga 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<0.05). In addition,the inhibition of the BK channel is also observed when 1 μM CBDis applied from the extracellular face of the cellular membrane inthe whole-cell configuration (% of inhibition: 48.3 ± 5.3, n=8). Ourresults indicate that CBD directly inhibits the BK channel, reducingits voltage dependence and delaying channel activation. These ef-fects could be involved in the probed anticonvulsant activity of thiscannabinoid adding a new target to CBD effects.