Inhibition of recombinant human T-type calcium channels by Delta9-tetrahydrocannabinol and cannabidiol.
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.
Ross
Hamish Redmond
HR
Pain Management Research Institute, Kolling Institute, University of Sydney at Royal North Shore Hospital, St Leonards, New South Wales 2065, Australia.
Napier
Ian
I
Connor
Mark
M
D018712:Analgesics, Non-Narcotic / Q000737:chemistry / Q000494:pharmacology*; D000818:Animals; D002118:Calcium / Q000378:metabolism; D020747:Calcium Channels, T-Type / Q000378:metabolism*; D002185:Cannabidiol / Q000737:chemistry / Q000494:pharmacology*; D002188:Cannabis / Q000737:chemistry; D002460:Cell Line; D004305:Dose-Response Relationship, Drug; D013759:Dronabinol / Q000737:chemistry / Q000494:pharmacology*; D015870:Gene Expression; D006801:Humans; D007700:Kinetics; D008564:Membrane Potentials / Q000187:drug effects*; D051379:Mice; D009475:Neurons, Afferent / Q000166:cytology / Q000502:physiology; D043884:Receptor, Cannabinoid, CB1 / Q000819:agonists / Q000235:genetics / Q000378:metabolism
D018712:Analgesics, Non-Narcotic; D020747:Calcium Channels, T-Type; D043884:Receptor, Cannabinoid, CB1; D002185:Cannabidiol; D013759:Dronabinol; D002118:Calcium