title: Cannabinoid- and lysophosphatidylinositol-sensitive receptor GPR55 boosts neurotransmitter release at central synapses.
abstract: G protein-coupled receptor (GPR) 55 is sensitive to certain cannabinoids, it is expressed in the brain and, in cell cultures, it triggers mobilization of intracellular Ca(2+). However, the adaptive neurobiological significance of GPR55 remains unknown. Here, we use acute hippocampal slices and combine two-photon excitation Ca(2+) imaging in presynaptic axonal boutons with optical quantal analysis in postsynaptic dendritic spines to find that GPR55 activation transiently increases release probability at individual CA3-CA1 synapses. The underlying mechanism involves Ca(2+) release from presynaptic Ca(2+) stores, whereas postsynaptic stores (activated by spot-uncaging of inositol 1,4,5-trisphosphate) remain unaffected by GPR55 agonists. These effects are abolished by genetic deletion of GPR55 or by the GPR55 antagonist cannabidiol, a constituent of Cannabis sativa. GPR55 shows colocalization with synaptic vesicle protein vesicular glutamate transporter 1 in stratum radiatum. Short-term potentiation of CA3-CA1 transmission after a short train of stimuli reveals a presynaptic, Ca(2+) store-dependent component sensitive to cannabidiol. The underlying cascade involves synthesis of phospholipids, likely in the presynaptic cell, but not the endocannabinoids 2-arachidonoylglycerol or anandamide. Our results thus unveil a signaling role for GPR55 in synaptic circuits of the brain.
authors.affiliation: Department of Clinical and Experimental Epilepsy, Institute of Neurology, University College London, London WC1N 3BG, United Kingdom.
authors.forename: Sergiy
authors.initials: S
authors.lastname: Sylantyev
authors.forename: Thomas P
authors.initials: TP
authors.lastname: Jensen
authors.forename: Ruth A
authors.initials: RA
authors.lastname: Ross
authors.forename: Dmitri A
authors.initials: DA
authors.lastname: Rusakov
mesh_terms: D000818:Animals; D056547:CA1 Region, Hippocampal / Q000166:cytology / Q000378:metabolism*; D056654:CA3 Region, Hippocampal / Q000166:cytology / Q000378:metabolism*; D002118:Calcium / Q000378:metabolism; D002185:Cannabidiol / Q000737:chemistry / Q000494:pharmacology; D002188:Cannabis / Q000737:chemistry; D015544:Inositol 1,4,5-Trisphosphate / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D042282:Microdissection; D018377:Neurotransmitter Agents / Q000378:metabolism*; D017729:Presynaptic Terminals / Q000378:metabolism; D051381:Rats; D043882:Receptors, Cannabinoid / Q000235:genetics / Q000378:metabolism*; D043562:Receptors, G-Protein-Coupled / Q000235:genetics / Q000378:metabolism*; D013570:Synaptic Membranes / Q000378:metabolism*; D009435:Synaptic Transmission / Q000187:drug effects / Q000502:physiology*
chemical_list: C526692:GPR55 protein, mouse; C568825:GPR55 protein, rat; D018377:Neurotransmitter Agents; D043882:Receptors, Cannabinoid; D043562:Receptors, G-Protein-Coupled; D002185:Cannabidiol; D015544:Inositol 1,4,5-Trisphosphate; D002118:Calcium