Lipid rafts regulate 2-arachidonoylglycerol metabolism and physiological activity in the striatum.
Several G protein-associated receptors and synaptic proteins function within lipid rafts, which are subdomains of the plasma membranes that contain high concentrations of cholesterol. In this study we addressed the possible role of lipid rafts in the control of endocannabinoid system in striatal slices. Disruption of lipid rafts following cholesterol depletion with methyl-beta-cyclodestrin (MCD) failed to affect synthesis and degradation of anandamide, while it caused a marked increase in the synthesis and concentration of 2-arachidonoylglycerol (2-AG), as well as in the binding activity of cannabinoid CB1 receptors. Surprisingly, endogenous 2-AG-mediated control of GABA transmission was not potentiated by MCD treatment and, in contrast, neither basal nor 3,5-Dihydroxyphenylglycine-stimulated 2-AG altered GABA synapses in cholesterol-depleted slices. Synaptic response to the cannabinoid CB1 receptor agonist HU210 was however intact in MCD-treated slices, indicating that reduced sensitivity of cannabinoid CB1 receptors does not explain why endogenous 2-AG is ineffective in inhibiting striatal GABA transmission after cholesterol depletion. Confocal microscopy analysis suggested that disruption of raft integrity by MCD might uncouple metabotropic glutamate 5-CB1 receptor interaction by altering the correct localization of both receptors in striatal neuron elements. In conclusion, our data indicate that disruption of raft integrity causes a complex alteration of the endocannabinoid signalling in the striatum.
Maccarrone
Mauro
M
Dipartimento di Scienze Biomediche, Università degli Studi di Teramo, Italy. mmaccarrone@unite.it
De Chiara
Valentina
V
Gasperi
Valeria
V
Viscomi
Maria Teresa
MT
Rossi
Silvia
S
Oddi
Sergio
S
Molinari
Marco
M
Musella
Alessandra
A
Finazzi-Agrò
Alessandro
A
Centonze
Diego
D
D000818:Animals; D001095:Arachidonic Acids / Q000378:metabolism*; D063385:Cannabinoid Receptor Modulators / Q000378:metabolism; D002784:Cholesterol / Q000378:metabolism; D003342:Corpus Striatum / Q000378:metabolism / Q000502:physiology*; D063388:Endocannabinoids; D005989:Glycerides / Q000378:metabolism*; D053444:Inhibitory Postsynaptic Potentials / Q000502:physiology; D021962:Membrane Microdomains / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL
D001095:Arachidonic Acids; D063385:Cannabinoid Receptor Modulators; D063388:Endocannabinoids; D005989:Glycerides; C094503:glyceryl 2-arachidonate; D002784:Cholesterol