Inhibition of human recombinant T-type calcium channels by the endocannabinoid N-arachidonoyl dopamine

Hamish R. Ross, Andrew J. Gilmore, Mark Connor*

*Corresponding author for this work

Research output: Contribution to journalArticle

45 Citations (Scopus)

Abstract

Background and purpose: N-arachidonoyl dopamine (NADA) has complex effects on nociception mediated via cannabinoid CB 1 receptors and the transient receptor potential vanilloid receptor 1 (TRPV1). Anandamide, the prototypic CB 1/TRPV1 agonist, also inhibits T-type voltage-gated calcium channel currents (I Ca). These channels are expressed by many excitable cells, including neurons involved in pain detection and processing. We sought to determine whether NADA and the prototypic arachidonoyl amino acid, N-arachidonoyl glycine (NAGly) modulate T-type I Ca Experimental approach: Human recombinant T-type I Ca (Ca V3 channels) expressed in HEK 293 cells and native mouse T-type I Ca were examined using standard whole-cell voltage clamp electrophysiology techniques. Key results: N-arachidonoyl dopamine completely inhibited Ca V3 channels with a rank order of potency (pEC 50) of Ca V3.3 (6.45) ≥ Ca V3.1 (6.29) > Ca V3.2 (5.95). NAGly (10 μmol·L -1) inhibited Ca V3 I Ca by approximately 50% or less. The effects of NADA and NAGly were voltage- but not use-dependent, and both compounds produced significant hyperpolarizing shifts in Ca V3 channel steady-state inactivation relationships. By contrast with anandamide, NADA and NAGly had modest effects on Ca V3 channel kinetics. Both NAGly and NADA inhibited native T-type I Ca in mouse sensory neurons. Conclusions and implications: N-arachidonoyl dopamine and NAGly increase the steady-state inactivation of Ca V3 channels, reducing the number of channels available to open during depolarization. These effects occur at NADA concentrations at or below to those affecting CB 1 and TRPV1 receptors. Together with anandamide, the arachidonoyl neurotransmitter amides, NADA and NAGly, represent a new family of endogenous T-type I Ca modulators.

Original languageEnglish
Pages (from-to)740-750
Number of pages11
JournalBritish Journal of Pharmacology
Volume156
Issue number5
DOIs
Publication statusPublished - Mar 2009
Externally publishedYes

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