Subunit-specific modulation of glycine receptors by cannabinoids and N-arachidonyl-glycine

Yang, Zhe, Aubrey, Karin R., Alroy, Iris, Harvey, Robert J., Vandenberg, Robert J. and Lynch, Joseph W. (2008) Subunit-specific modulation of glycine receptors by cannabinoids and N-arachidonyl-glycine. Biochemical Pharmacology, 76 8: 1014-1023. doi:10.1016/j.bcp.2008.07.037


Author Yang, Zhe
Aubrey, Karin R.
Alroy, Iris
Harvey, Robert J.
Vandenberg, Robert J.
Lynch, Joseph W.
Title Subunit-specific modulation of glycine receptors by cannabinoids and N-arachidonyl-glycine
Journal name Biochemical Pharmacology   Check publisher's open access policy
ISSN 0006-2952
1873-2968
Publication date 2008-10-15
Year available 2008
Sub-type Article (original research)
DOI 10.1016/j.bcp.2008.07.037
Open Access Status Not Open Access
Volume 76
Issue 8
Start page 1014
End page 1023
Total pages 10
Editor S. J. Enna
Place of publication New York, N.Y. U.S.A.
Publisher Elsevier
Language eng
Subject C1
110903 Central Nervous System
920111 Nervous System and Disorders
Abstract Glycine receptors (GlyRs) mediate inhibitory neurotransmission in spinal cord motor and pain sensory neurons. Recent studies demonstrated apparently contradictory (potentiating versus inhibitory) effects of the endocannabinoid anandamide on these receptors. The present study characterised the effects of cannabinoid agonists on alpha1, alpha1beta, alpha2 and alpha3 GlyRs recombinantly expressed in HEK293 cells with the aims of reconciling effects of cannabinoids on these receptor subtypes and to establish the potential of different GlyR isoforms as novel physiological or analgesic targets for cannabinoids. The compounds investigated were anandamide, HU-210, HU-308, WIN55,212-2 and the endogenous non-cannabinoid, N-arachidonyl-glycine. The latter compound was chosen due to the structural similarity with anandamide and known analgesic actions in the spinal cord. Recombinant alpha1 and alpha1beta GlyRs were potentiated by anandamide and HU-210 at submicromolar concentrations, whereas WIN55,212-2 had no effect and HU-308 produced only weak inhibition. By contrast, N-arachidonyl-glycine exerted complex effects including both potentiation and inhibition. Anandamide had no effect at alpha2 or alpha3 GlyRs although the other cannabinoids produced potent inhibition. On alpha2 GlyRs, the inhibitory potency sequence was HU-210=WIN55,212-2>HU-308>N-arachidonyl-glycine but on alpha3 GlyRs it was HU-210=WIN55212=HU-308>N-arachidonyl-glycine. These results suggest that alpha1, alpha2 and alpha3 containing GlyRs exhibit distinct pharmacological profiles for cannabinoids. We conclude that cannabinoid agonists may be useful as pharmacological tools for selectively inhibiting alpha2 and alpha3 GlyRs. Our results also establish GlyRs as potential novel targets for endogenous and exogenous cannabinoids.
Formatted abstract
 Glycine receptors (GlyRs) mediate inhibitory neurotransmission in spinal cord motor and pain sensory neurons. Recent studies demonstrated apparently contradictory (potentiating versus inhibitory) effects of the endocannabinoid anandamide on these receptors. The present study characterised the effects of cannabinoid agonists on α1, α1β, α2 and α3 GlyRs recombinantly expressed in HEK293 cells with the aims of reconciling effects of cannabinoids on these receptor subtypes and to establish the potential of different GlyR isoforms as novel physiological or analgesic targets for cannabinoids. The compounds investigated were anandamide, HU-210, HU-308, WIN55,212-2 and the endogenous non-cannabinoid, N-arachidonyl-glycine. The latter compound was chosen due to the structural similarity with anandamide and known analgesic actions in the spinal cord. Recombinant α1 and α1β GlyRs were potentiated by anandamide and HU-210 at submicromolar concentrations, whereas WIN55,212-2 had no effect and HU-308 produced only weak inhibition. By contrast, N-arachidonyl-glycine exerted complex effects including both potentiation and inhibition. Anandamide had no effect at α2 or α3 GlyRs although the other cannabinoids produced potent inhibition. On α2 GlyRs, the inhibitory potency sequence was HU-210 = WIN55,212-2 > HU-308 > N-arachidonyl-glycine but on α3 GlyRs it was HU-210 = WIN55212 = HU-308 > N-arachidonyl-glycine. These results suggest that α1, α2 and α3 containing GlyRs exhibit distinct pharmacological profiles for cannabinoids. We conclude that cannabinoid agonists may be useful as pharmacological tools for selectively inhibiting α2 and α3 GlyRs. Our results also establish GlyRs as potential novel targets for endogenous and exogenous cannabinoids.
Keyword Cys-loop receptor
Ligand-gated ion channel
Nociception
Analgesia
Neurotransmission
Endocannabinoid
HU-210
HU-308
WIN55
212-2
Anandamide
N-arachidonyl-glycine
Q-Index Code C1
Q-Index Status Confirmed Code
Grant ID G0500833
G0500833(74778)
Institutional Status UQ
Additional Notes Available online 7 August 2008

 
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Created: Thu, 19 Mar 2009, 22:13:52 EST by Debra McMurtrie on behalf of Queensland Brain Institute