Inhibition of Recombinant Human T-type Calcium Channels by Delta9-tetrahydrocannabinol and Cannabidiol

Overview

Journal J Biol Chem

Specialty Biochemistry

Date 2008 Apr 9

PMID 18390906

Citations 86

Authors

Hamish Redmond Ross

Ian Napier

Mark Connor

Affiliations

Soon will be listed here.

Abstract

Delta(9)-Tetrahydrocannabinol (THC) and cannabidiol (CBD) are the most prevalent biologically active constituents of Cannabis sativa. THC is the prototypic cannabinoid CB1 receptor agonist and is psychoactive and analgesic. CBD is also analgesic, but it is not a CB1 receptor agonist. Low voltage-activated T-type calcium channels, encoded by the Ca(V)3 gene family, regulate the excitability of many cells, including neurons involved in nociceptive processing. We examined the effects of THC and CBD on human Ca(V)3 channels stably expressed in human embryonic kidney 293 cells and T-type channels in mouse sensory neurons using whole-cell, patch clamp recordings. At moderately hyperpolarized potentials, THC and CBD inhibited peak Ca(V)3.1 and Ca(V)3.2 currents with IC(50) values of approximately 1 mum but were less potent on Ca(V)3.3 channels. THC and CBD inhibited sensory neuron T-type channels by about 45% at 1 mum. However, in recordings made from a holding potential of -70 mV, 100 nm THC or CBD inhibited more than 50% of the peak Ca(V)3.1 current. THC and CBD produced a significant hyperpolarizing shift in the steady state inactivation potentials for each of the Ca(V)3 channels, which accounts for inhibition of channel currents. Additionally, THC caused a modest hyperpolarizing shift in the activation of Ca(V)3.1 and Ca(V)3.2. THC but not CBD slowed Ca(V)3.1 and Ca(V)3.2 deactivation and inactivation kinetics. Thus, THC and CBD inhibit Ca(V)3 channels at pharmacologically relevant concentrations. However, THC, but not CBD, may also increase the amount of calcium entry following T-type channel activation by stabilizing open states of the channel.

Citing Articles

Cannabidiol (CBD) Acts as an Antioxidant on , Resulting in Reduced Metabolic Activity, Loss of Survivability, and Elimination of Biofilms.

Sionov R, Korem M, Polacheck I, Steinberg D Antibiotics (Basel). 2025; 14(2).

PMID: 40001381 PMC: 11851883. DOI: 10.3390/antibiotics14020136.

Nav1.8, an analgesic target for nonpsychotomimetic phytocannabinoids.

Ghovanloo M, Tyagi S, Zhao P, Waxman S Proc Natl Acad Sci U S A. 2025; 122(4):e2416886122.

PMID: 39835903 PMC: 11789019. DOI: 10.1073/pnas.2416886122.

Endocannabinoid regulation of inward rectifier potassium (Kir) channels.

Mayar S, Borbuliak M, Zoumpoulakis A, Bouceba T, Labonte M, Ahrari A Front Pharmacol. 2024; 15:1439767.

PMID: 39253376 PMC: 11381239. DOI: 10.3389/fphar.2024.1439767.

Local activation of CB1 receptors by synthetic and endogenous cannabinoids dampens burst firing mode of reticular thalamic nucleus neurons in rats under ketamine anesthesia.

Aguirre-Rodriguez C, Delgado A, Alatorre A, Oviedo-Chavez A, Martinez-Escudero J, Barrientos R Exp Brain Res. 2024; 242(9):2137-2157.

PMID: 38980339 DOI: 10.1007/s00221-024-06889-6.

An Overview of Cannabidiol as a Multifunctional Drug: Pharmacokinetics and Cellular Effects.

Martinez Naya N, Kelly J, Corna G, Golino M, Polizio A, Abbate A Molecules. 2024; 29(2).

PMID: 38257386 PMC: 10818442. DOI: 10.3390/molecules29020473.

References

Zimmer A, Zimmer A, Hohmann A, Herkenham M, Bonner T . Increased mortality, hypoactivity, and hypoalgesia in cannabinoid CB1 receptor knockout mice. Proc Natl Acad Sci U S A. 1999; 96(10):5780-5. PMC: 21937. DOI: 10.1073/pnas.96.10.5780. View

Compton D, Johnson M, Melvin L, Martin B . Pharmacological profile of a series of bicyclic cannabinoid analogs: classification as cannabimimetic agents. J Pharmacol Exp Ther. 1992; 260(1):201-9. View

Caulfield M, Brown D . Cannabinoid receptor agonists inhibit Ca current in NG108-15 neuroblastoma cells via a pertussis toxin-sensitive mechanism. Br J Pharmacol. 1992; 106(2):231-2. PMC: 1907498. DOI: 10.1111/j.1476-5381.1992.tb14321.x. View

Barann M, Molderings G, Bruss M, Bonisch H, Urban B, Gothert M . Direct inhibition by cannabinoids of human 5-HT3A receptors: probable involvement of an allosteric modulatory site. Br J Pharmacol. 2002; 137(5):589-96. PMC: 1573528. DOI: 10.1038/sj.bjp.0704829. View

Mura P, Kintz P, Dumestre V, Raul S, Hauet T . THC can be detected in brain while absent in blood. J Anal Toxicol. 2005; 29(8):842-3. DOI: 10.1093/jat/29.8.842. View

Tarabova B, Kurejova M, Sulova Z, Drabova M, Lacinova L . Inorganic mercury and methylmercury inhibit the Cav3.1 channel expressed in human embryonic kidney 293 cells by different mechanisms. J Pharmacol Exp Ther. 2005; 317(1):418-27. DOI: 10.1124/jpet.105.095463. View

Cribbs L, Gomora J, Daud A, Lee J, Perez-Reyes E . Molecular cloning and functional expression of Ca(v)3.1c, a T-type calcium channel from human brain. FEBS Lett. 2000; 466(1):54-8. DOI: 10.1016/s0014-5793(99)01756-1. View

Tao Q, Abood M . Mutation of a highly conserved aspartate residue in the second transmembrane domain of the cannabinoid receptors, CB1 and CB2, disrupts G-protein coupling. J Pharmacol Exp Ther. 1998; 285(2):651-8. View

Jordt S, Bautista D, Chuang H, McKemy D, Zygmunt P, Hogestatt E . Mustard oils and cannabinoids excite sensory nerve fibres through the TRP channel ANKTM1. Nature. 2004; 427(6971):260-5. DOI: 10.1038/nature02282. View

10.

Varvel S, Bridgen D, Tao Q, Thomas B, Martin B, Lichtman A . Delta9-tetrahydrocannbinol accounts for the antinociceptive, hypothermic, and cataleptic effects of marijuana in mice. J Pharmacol Exp Ther. 2005; 314(1):329-37. DOI: 10.1124/jpet.104.080739. View

11.

Feinberg I, Jones R, Walker J, Cavness C, Floyd T . Effects of marijuana extract and tetrahydrocannabinol on electroencephalographic sleep patterns. Clin Pharmacol Ther. 1976; 19(6):782-94. DOI: 10.1002/cpt1976196782. View

12.

CHEMIN J, Monteil A, Perez-Reyes E, Nargeot J, Lory P . Direct inhibition of T-type calcium channels by the endogenous cannabinoid anandamide. EMBO J. 2001; 20(24):7033-40. PMC: 125779. DOI: 10.1093/emboj/20.24.7033. View

13.

Pertwee R . The diverse CB1 and CB2 receptor pharmacology of three plant cannabinoids: delta9-tetrahydrocannabinol, cannabidiol and delta9-tetrahydrocannabivarin. Br J Pharmacol. 2007; 153(2):199-215. PMC: 2219532. DOI: 10.1038/sj.bjp.0707442. View

14.

Kim D, Park D, Choi S, Lee S, Sun M, Kim C . Thalamic control of visceral nociception mediated by T-type Ca2+ channels. Science. 2003; 302(5642):117-9. DOI: 10.1126/science.1088886. View

15.

Jarai Z, Wagner J, Varga K, Lake K, Compton D, Martin B . Cannabinoid-induced mesenteric vasodilation through an endothelial site distinct from CB1 or CB2 receptors. Proc Natl Acad Sci U S A. 1999; 96(24):14136-41. PMC: 24203. DOI: 10.1073/pnas.96.24.14136. View

16.

PEREZ-REYES M, Timmons M, Davis K, Wall E . A comparison of the pharmacological activity in man of intravenously administered delta9-tetrahydrocannabinol, cannabinol, and cannabidiol. Experientia. 1973; 29(11):1368-9. DOI: 10.1007/BF01922823. View

17.

Todorovic S, Jevtovic-Todorovic V, Meyenburg A, Mennerick S, Perez-Reyes E, Romano C . Redox modulation of T-type calcium channels in rat peripheral nociceptors. Neuron. 2001; 31(1):75-85. DOI: 10.1016/s0896-6273(01)00338-5. View

18.

Ryberg E, Larsson N, Sjogren S, Hjorth S, Hermansson N, Leonova J . The orphan receptor GPR55 is a novel cannabinoid receptor. Br J Pharmacol. 2007; 152(7):1092-101. PMC: 2095107. DOI: 10.1038/sj.bjp.0707460. View

19.

Clark A, Ware M, Yazer E, Murray T, Lynch M . Patterns of cannabis use among patients with multiple sclerosis. Neurology. 2004; 62(11):2098-100. DOI: 10.1212/01.wnl.0000127707.07621.72. View

20.

Hall W, Swift W . The THC content of cannabis in Australia: evidence and implications. Aust N Z J Public Health. 2000; 24(5):503-8. DOI: 10.1111/j.1467-842x.2000.tb00500.x. View