Neuron-type specific cannabinoid-mediated G protein signalling in mouse hippocampus.
J. Neurochem.. 2013-02-13; 124(6): 795-807
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1. J Neurochem. 2013 Mar;124(6):795-807. doi: 10.1111/jnc.12137. Epub 2013 Feb 13.
Neuron-type specific cannabinoid-mediated G protein signalling in mouse
Steindel F(1), Lerner R, Häring M, Ruehle S, Marsicano G, Lutz B, Monory K.
(1)Institute of Physiological Chemistry, University Medical Center of the
Johannes Gutenberg University Mainz, Mainz, Germany.
Type 1 cannabinoid receptor (CB1) is expressed in different neuronal populations
in the mammalian brain. In particular, CB1 on GABAergic or glutamatergic neurons
exerts different functions and display different pharmacological properties in
vivo. This suggests the existence of neuron-type specific signalling pathways
activated by different subpopulations of CB1. In this study, we analysed CB1
expression, binding and signalling in the hippocampus of conditional mutant mice,
bearing CB1 deletion in GABAergic (GABA-CB1-KO mice) or cortical glutamatergic
neurons (Glu-CB1-KO mice). Compared to their wild-type littermates, Glu-CB1-KO
displayed a small decrease of CB1 mRNA amount, immunoreactivity and [³H]CP55,940
binding. Conversely, GABA-CB1-KO mice showed a drastic reduction of these
parameters, confirming that CB1 is present at much higher density on hippocampal
GABAergic interneurons than glutamatergic neurons. Surprisingly, however,
saturation analysis of HU210-stimulated [(35) S]GTPγS binding demonstrated that
‘glutamatergic’ CB1 is more efficiently coupled to G protein signalling than
‘GABAergic’ CB1. Thus, the minority of CB1 on glutamatergic neurons is
paradoxically several fold more strongly coupled to G protein signalling than
‘GABAergic’ CB1. This selective signalling mechanism raises the possibility of
designing novel cannabinoid ligands that differentially activate only a subset of
physiological effects of CB1 stimulation, thereby optimizing therapeutic action.
© 2013 International Society for Neurochemistry.
PMID: 23289830 [Indexed for MEDLINE]