Cannabidiol Modulates M-Type K+ and Hyperpolarization-Activated Cation Currents

Abstract

Cannabidiol (CBD) is a naturally occurring compound found in the Cannabis plant that is known for its potential therapeutic effects. However, its impact on membrane ionic currents remains a topic of debate. This study aimed to investigate how CBD modifies various types of ionic currents in pituitary GH3 cells. Results showed that exposure to CBD led to a concentration-dependent decrease in M-type K+ currents (IK(M)), with an IC50 of 3.6 μM, and caused the quasi-steady-state activation curve of the current to shift to a more depolarized potential with no changes in the curve’s steepness. The CBD-mediated block of IK(M) was not reversed by naloxone, suggesting that it was not mediated by opioid receptors. The IK(M) elicited by pulse-train stimulation was also decreased upon exposure to CBD. The magnitude of erg-mediated K+ currents was slightly reduced by adding CBD (10 μM), while the density of voltage-gated Na+ currents elicited by a short depolarizing pulse was not affected by it. Additionally, CBD decreased the magnitude of hyperpolarization-activated cation currents (Ih) with an IC50 of 3.3 μM, and the decrease was reversed by oxaliplatin. The quasi-steady-state activation curve of Ih was shifted in the leftward direction with no changes in the slope factor of the curve. CBD also diminished the strength of voltage-dependent hysteresis on Ih elicited by upright isosceles-triangular ramp voltage. Collectively, these findings suggest that CBD’s modification of ionic currents presented herein is independent of cannabinoid or opioid receptors and may exert a significant impact on the functional activities of excitable cells occurring in vitro or in vivo.

Direct Inhibition of BK Channels by Cannabidiol, One of the Principal Therapeutic Cannabinoids Derived from Cannabis sativa

“…Controversially, CBD inhibits the M-type current in GH3 tumor cells but activates the same current in rat hippocampal neurons. 22,33 The difference may reflect distinct channel isoforms expressed in each cell type. In HEK cells, CBD directly activates the heteromeric Kv7.2/7.3 channel.…”

Assessing the Impact of Agents with Antiviral Activities on Transmembrane Ionic Currents: Exploring Possible Unintended Actions

“…Among KCNQ genes, KCNQ2 and KCNQ3 subunits heteromultimerize to form the channels responsible for I K(M) in neurons [37]. In recent research conducted on pituitary GH 3 cells, it was demonstrated that exposure to CBD leads to the suppression in the amplitudes of I K(M) and the hyperpolarization-activated cation current (I h ), with the corresponding IC 50 values of 3.6 and 3.3 µM, respectively [14]. The biophysical property of I h is distinctive, marked by its slow activation kinetics during sustained hyperpolarization [38,39].…”