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J. Biol. Chem., Vol. 283, Issue 23, 16124-16134, June 6, 2008

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Inhibition of Recombinant Human T-type Calcium Channels by ⁹-Tetrahydrocannabinol and Cannabidiol^*

From the Pain Management Research Institute, Kolling Institute, University of Sydney at Royal North Shore Hospital, St Leonards, New South Wales 2065, Australia

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_V3 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_V3 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_V3.1 and Ca_V3.2 currents with IC₅₀ values of 1 µM but were less potent on Ca_V3.3 channels. THC and CBD inhibited sensory neuron T-type channels by about 45% at 1 µM. However, in recordings made from a holding potential of -70 mV, 100 nM THC or CBD inhibited more than 50% of the peak Ca_V3.1 current. THC and CBD produced a significant hyperpolarizing shift in the steady state inactivation potentials for each of the Ca_V3 channels, which accounts for inhibition of channel currents. Additionally, THC caused a modest hyperpolarizing shift in the activation of Ca_V3.1 and Ca_V3.2. THC but not CBD slowed Ca_V3.1 and Ca_V3.2 deactivation and inactivation kinetics. Thus, THC and CBD inhibit Ca_V3 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.

Received for publication, August 24, 2007 , and in revised form, March 27, 2008.

^* This work was supported in part by National Health & Medical Research Council of Australia Project 402564 (to M. C.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ Supported by a University of Sydney postgraduate award and a Kolling Institute Award.

² Supported by an Australian Postgraduate Award and a Ramsay Healthcare Award.

³ To whom correspondence should be addressed: Pain Management Research Inst., Level 5, Main Block, Royal North Shore Hospital, St Leonards, New South Wales 2065, Australia. Tel.: 61-2-9926-518; Fax: 61-2-9906-4079; E-mail: markc{at}med.usyd.edu.au.

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