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Inhibition of human recombinant T-type calcium channels by the endocannabinoid N-arachidonoyl dopamine Ross HR; Gilmore AJ; Connor MBr J Pharmacol 2009[Mar]; 156 (5): 740-50BACKGROUND 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(V)3 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(V)3 channels with a rank order of potency (pEC(50)) of Ca(V)3.3 (6.45) > or = Ca(V)3.1 (6.29) > Ca(V)3.2 (5.95). NAGly (10 micromol.L(-1)) inhibited Ca(V)3 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(V)3 channel steady-state inactivation relationships. By contrast with anandamide, NADA and NAGly had modest effects on Ca(V)3 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(V)3 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.|*Endocannabinoids[MESH]|Analgesics/*pharmacology[MESH]|Animals[MESH]|Arachidonic Acids/*pharmacology[MESH]|Calcium Channel Blockers/*pharmacology[MESH]|Calcium Channels, T-Type/*physiology[MESH]|Cannabinoid Receptor Modulators/*pharmacology[MESH]|Cells, Cultured[MESH]|Dopamine/*analogs & derivatives/pharmacology[MESH]|Glycine/analogs & derivatives/pharmacology[MESH]|Humans[MESH]|Kinetics[MESH]|Male[MESH]|Membrane Potentials[MESH]|Mice[MESH]|Mice, Inbred C57BL[MESH]|Patch-Clamp Techniques[MESH]|Recombinant Proteins/antagonists & inhibitors[MESH]|Sensory Receptor Cells/drug effects/physiology[MESH]|Trigeminal Ganglion/cytology[MESH] |
