Modulation of recombinant human T-type calcium channels by Δ9-tetrahydrocannabinolic acid in vitro

Somayeh Mirlohi, Chris Bladen, Marina Santiago, Mark Connor*

*Corresponding author for this work

    Research output: Contribution to journalArticlepeer-review

    7 Citations (Scopus)


    Introduction: Low voltage-activated T-type calcium channels (T-type ICa), CaV3.1, CaV3.2, and CaV3.3, are opened by small depolarizations from the resting membrane potential in many cells and have been associated with neurological disorders, including absence epilepsy and pain. Δ9-tetrahydrocannabinol (THC) is the principal psychoactive compound in Cannabis and also directly modulates T-type ICa; however, there is no information about functional activity of most phytocannabinoids on T-type calcium channels, including Δ9-tetrahydrocannabinolic acid (THCA), the natural nonpsychoactive precursor of THC. The aim of this work was to characterize THCA effects on T-type calcium channels.

    Materials and Methods: We used HEK293 Flp-In-TREx cells stably expressing CaV3.1, 3.2, or 3.3. Whole-cell patch clamp recordings were made to investigate cannabinoid modulation of ICa.

    Results: THCA and THC inhibited the peak current amplitude CaV3.1 with pEC50s of 6.0±0.7 and 5.6±0.4, respectively. THC (1 μM) or THC produced a significant negative shift in half activation and inactivation of CaV3.1, and both drugs prolonged CaV3.1 deactivation kinetics. THCA (10 μM) inhibited CaV3.2 by 53%±4%, and both THCA and THC produced a substantial negative shift in the voltage for half inactivation and modest negative shift in half activation of CaV3.2. THC prolonged the deactivation time of CaV3.2, while THCA did not. THCA inhibited the peak current of CaV3.3 by 43%±2% (10 μM) but did not notably affect CaV3.3 channel activation or inactivation; however, THC caused significant hyperpolarizing shift in CaV3.3 steady-state inactivation.

    Discussion: THCA modulated T-type ICa currents in vitro, with significant modulation of kinetics and voltage dependence at low μM concentrations. This study suggests that THCA may have potential for therapeutic use in pain and epilepsy through T-type calcium channel modulation without the unwanted psychoactive effects associated with THC.
    Original languageEnglish
    Pages (from-to)34-45
    Number of pages12
    JournalCannabis and Cannabinoid Research
    Issue number1
    Early online date21 Jan 2021
    Publication statusPublished - Feb 2022


    • Δ9 - tetrahydrocannabinol
    • Δ9 - tetrahydrocannabinol acid
    • electrophysiology
    • epilepsy
    • pain
    • phytocannabinoids
    • T-type calcium channels


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