Astrocytic GPR55 receptors promote glycolysis.

Abstract

BACKGROUND: The endocannabinoid system is closely associated with systemic and cellular energy metabolism in mammals. We previously demonstrated that the cannabinoid receptors CB1 and CB2 play important roles in cerebral glucose metabolism. GPR55, a paracannabinoid receptor, has been implicated in systemic metabolic regulation and in diseases such as intractable epilepsy, diabetes, and cancer. In the present study, we investigated whether GPR55 also influences brain glucose metabolism. METHODS: Acute hippocampal and cortical slices and primary astrocytic cultures from C57BL/6 mice and Wistar rats were used. Quantitative polymerase chain reaction (qPCR) was used to assess Cnr1 and Gpr55 gene expression levels, and [³H]deoxyglucose/[¹⁴C]-U-glucose uptake assays, high-resolution respirometry using the Oroboros O2k system, and proton nuclear magnetic resonance ([¹H]-NMR) spectroscopy were employed to assess metabolic activity upon receptor activation. RESULTS: qPCR analysis revealed that Cnr1 mRNA dominated in neurons, whereas Gpr55 was predominantly expressed in primary astrocytes. Δ⁹-Tetrahydrocannabinol (Δ⁹-THC), the GPR55-selective synthetic agonist O-1602, the endogenous GPR55 agonists, L-α-lysophosphatidylinositol (LPI) and palmitoylethanolamide (PEA), together with the mixed CB1 receptor antagonist/GPR55 agonist AM251, invariably and significantly stimulated glucose uptake and metabolism in brain preparations at nanomolar concentrations ex vivo. The GPR55-selective antagonist CID16020046 (1 µM) abolished the effects of the GPR55 agonists, as did pretreatment with the cytosolic Ca2+ chelator BAPTA-AM (30 µM). While LPI did not alter oxidative metabolism in either astrocytes or neurons, it selectively stimulated glycolysis and lactate release in astrocytes. CONCLUSIONS: Our findings reveal a novel role for GPR55 in astrocytes. By enhancing glycolytic activity in these cells, GPR55 is likely poised to support, even if indirectly, the energy demands of synaptic transmission.