QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text Full Text (PDF) Submit a response Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Guo, J. Articles by Ikeda, S. R. Search for Related Content PubMed PubMed Citation Articles by Guo, J. Articles by Ikeda, S. R.

Endocannabinoids Modulate N-Type Calcium Channels and G-Protein-Coupled Inwardly Rectifying Potassium Channels via CB1 Cannabinoid Receptors Heterologously Expressed in Mammalian Neurons

Laboratory of Molecular Physiology, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, Maryland

Endocannabinoids may serve as retrograde messengers to inhibit neurotransmitter release during depolarization-induced suppression of inhibition (DSI) or excitation (DSE). We therefore tested whether endocannabinoids inhibit N-type voltage-dependent Ca²⁺ channels by activating G_i/o-protein-coupled CB1 cannabinoid receptors (CB1R)—a possible mechanism underlying DSI/DSE. Three putative endocannabinoids [2-arachidonylglycerol (2-AG), 2-arachidonyl glycerol ether (2-AGE), and anandamide (AEA)] and the cannabimimetic aminoalkylindole WIN 55,212-2 (WIN) inhibited whole-cell Ca²⁺ currents in rat sympathetic neurons previously injected with cDNA encoding a human CB1R. Agonist-mediated Ca²⁺ current inhibition was blocked by a selective CB1R antagonist [SR141716A, N-(piperidin-1-yl)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboximide hydrochloride] and pertussis toxin (PTX) pretreatment. The rank order of potency was WIN (IC₅₀ = 2 nM) > 2-AGE (350 nM) 2-AG (480 nM) > AEA (3 µM), with each agonist displaying similar efficacy (approximately 50% maximal inhibition). Increasing CB1R expression level significantly enhanced AEA potency. AEA (10 µM) also inhibited Ca²⁺ channels in a voltage-independent, CB1R-independent, and PTX-insensitive manner, whereas 2-AG and 2-AGE were devoid of this activity. All three endocannabinoids activated G-protein-coupled inwardly rectifying potassium (GIRK) channels, GIRK1/4, heterologously expressed in sympathetic neurons. These results suggest a mechanism by which endocannibinoids might influence presynaptic function.

Address correspondence to: Stephen R. Ikeda, M.D., Ph.D., Laboratory of Molecular Physiology, National Institute on Alcohol Abuse and Alcoholism, Park Building Room 150, 12420 Parklawn Drive MSC 8115, Bethesda, MD 20892-8815. E-mail: sikeda{at}mail.nih.gov

This article has been cited by other articles:

				P. W. Wacnik, K. M. Luhr, R. H. Hill, H.-G. Ljunggren, K. Kristensson, and M. Svensson Cannabinoids Affect Dendritic Cell (DC) Potassium Channel Function and Modulate DC T Cell Stimulatory Capacity J. Immunol., September 1, 2008; 181(5): 3057 - 3066. [Abstract] [Full Text] [PDF]

				J. Guo, D. J. Williams, and S. R. Ikeda N-Arachidonoyl L-Serine, a Putative Endocannabinoid, Alters the Activation of N-Type Ca2+ Channels in Sympathetic Neurons J Neurophysiol, August 1, 2008; 100(2): 1147 - 1151. [Abstract] [Full Text] [PDF]

				A. Sheinin, G. Talani, M. I. Davis, and D. M. Lovinger Endocannabinoid- and mGluR5-Dependent Short-Term Synaptic Depression in an Isolated Neuron/Bouton Preparation From the Hippocampal CA1 Region J Neurophysiol, August 1, 2008; 100(2): 1041 - 1052. [Abstract] [Full Text] [PDF]

				J. Guo, D. J. Williams, H. L. Puhl III, and S. R. Ikeda Inhibition of N-Type Calcium Channels by Activation of GPR35, an Orphan Receptor, Heterologously Expressed in Rat Sympathetic Neurons J. Pharmacol. Exp. Ther., January 1, 2008; 324(1): 342 - 351. [Abstract] [Full Text] [PDF]

				S. Oka, S. Arai, K. Waku, A. Tokumura, and T. Sugiura Depolarization-induced Rapid Generation of 2-Arachidonoylglycerol, an Endogenous Cannabinoid Receptor Ligand, in Rat Brain Synaptosomes J. Biochem., May 1, 2007; 141(5): 687 - 697. [Abstract] [Full Text] [PDF]

				A. Neu, C. Foldy, and I. Soltesz Postsynaptic origin of CB1-dependent tonic inhibition of GABA release at cholecystokinin-positive basket cell to pyramidal cell synapses in the CA1 region of the rat hippocampus J. Physiol., January 1, 2007; 578(1): 233 - 247. [Abstract] [Full Text] [PDF]

				P. Pacher, S. Batkai, and G. Kunos The Endocannabinoid System as an Emerging Target of Pharmacotherapy Pharmacol. Rev., September 1, 2006; 58(3): 389 - 462. [Abstract] [Full Text] [PDF]

				H. H. Yin and D. M. Lovinger Frequency-specific and D2 receptor-mediated inhibition of glutamate release by retrograde endocannabinoid signaling PNAS, May 23, 2006; 103(21): 8251 - 8256. [Abstract] [Full Text] [PDF]

				P. J. Zhu and D. M. Lovinger Retrograde Endocannabinoid Signaling in a Postsynaptic Neuron/Synaptic Bouton Preparation from Basolateral Amygdala J. Neurosci., June 29, 2005; 25(26): 6199 - 6207. [Abstract] [Full Text] [PDF]