title: Lactate receptor sites link neurotransmission, neurovascular coupling, and brain energy metabolism.
abstract: The G-protein-coupled lactate receptor, GPR81 (HCA1), is known to promote lipid storage in adipocytes by downregulating cAMP levels. Here, we show that GPR81 is also present in the mammalian brain, including regions of the cerebral neocortex and hippocampus, where it can be activated by physiological concentrations of lactate and by the specific GPR81 agonist 3,5-dihydroxybenzoate to reduce cAMP. Cerebral GPR81 is concentrated on the synaptic membranes of excitatory synapses, with a postsynaptic predominance. GPR81 is also enriched at the blood-brain-barrier: the GPR81 densities at endothelial cell membranes are about twice the GPR81 density at membranes of perivascular astrocytic processes, but about one-seventh of that on synaptic membranes. There is only a slight signal in perisynaptic processes of astrocytes. In synaptic spines, as well as in adipocytes, GPR81 immunoreactivity is located on subplasmalemmal vesicular organelles, suggesting trafficking of the protein to and from the plasma membrane. The results indicate roles of lactate in brain signaling, including a neuronal glucose and glycogen saving response to the supply of lactate. We propose that lactate, through activation of GPR81 receptors, can act as a volume transmitter that links neuronal activity, cerebral energy metabolism and energy substrate availability.
authors.affiliation: The Brain and Muscle Energy Group, Department of Neuroscience and Pharmacology, Center for Healthy Aging, Faculty of Health Sciences, University of Copenhagen, Copenhagen, Denmark.
authors.forename: Knut H
authors.initials: KH
authors.lastname: Lauritzen
authors.affiliation: The Brain and Muscle Energy Group, Glio- and Neurotransmitter Group, Synaptic Neurochemistry Lab, Department of Anatomy and Centre for Molecular Biology and Neuroscience/SERTA Healthy Brain Aging, Institute of Basic Medical Sciences, University of Oslo, Oslo, Norway.
authors.forename: Cecilie
authors.initials: C
authors.lastname: Morland
authors.affiliation: Glio- and Neurotransmitter Group, Synaptic Neurochemistry Lab, Department of Anatomy and Centre for Molecular Biology and Neuroscience/SERTA Healthy Brain Aging, Institute of Basic Medical Sciences, University of Oslo, Oslo, Norway.
authors.forename: Maja
authors.initials: M
authors.lastname: Puchades
authors.affiliation: The Brain and Muscle Energy Group, Department of Neuroscience and Pharmacology, Center for Healthy Aging, Faculty of Health Sciences, University of Copenhagen, Copenhagen, Denmark.
authors.forename: Signe
authors.initials: S
authors.lastname: Holm-Hansen
authors.affiliation: Institute for Surgical Research, Oslo University Hospital, Oslo, Norway.
authors.forename: Else Marie
authors.initials: EM
authors.lastname: Hagelin
authors.affiliation: The Brain and Muscle Energy Group, Department of Neuroscience and Pharmacology, Center for Healthy Aging, Faculty of Health Sciences, University of Copenhagen, Copenhagen, Denmark.
authors.forename: Fredrik
authors.initials: F
authors.lastname: Lauritzen
authors.affiliation: Institute for Surgical Research, Oslo University Hospital, Oslo, Norway, Center for Heart Failure Research.
authors.forename: Håvard
authors.initials: H
authors.lastname: Attramadal
authors.affiliation: The Brain and Muscle Energy Group, Glio- and Neurotransmitter Group, Synaptic Neurochemistry Lab, Department of Anatomy and Centre for Molecular Biology and Neuroscience/SERTA Healthy Brain Aging, Institute of Basic Medical Sciences, University of Oslo, Oslo, Norway.
authors.forename: Jon
authors.initials: J
authors.lastname: Storm-Mathisen
authors.affiliation: Department of Neuroscience and Pharmacology, Center for Healthy Aging, Faculty of Health Sciences, University of Copenhagen, Copenhagen, Denmark.
authors.forename: Albert
authors.initials: A
authors.lastname: Gjedde
authors.affiliation: The Brain and Muscle Energy Group, Department of Neuroscience and Pharmacology, Center for Healthy Aging, Faculty of Health Sciences, University of Copenhagen, Copenhagen, Denmark, Institute of Oral Biology, University of Oslo, Norway.
authors.forename: Linda H
authors.initials: LH
authors.lastname: Bergersen
mesh_terms: D017667:Adipocytes / Q000378:metabolism; D000818:Animals; D001253:Astrocytes / Q000378:metabolism; D001921:Brain / Q000098:blood supply / Q000378:metabolism* / Q000648:ultrastructure; D002531:Cerebellum / Q000378:metabolism / Q000648:ultrastructure; D000242:Cyclic AMP / Q000378:metabolism; D004734:Energy Metabolism; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism / Q000648:ultrastructure; D019344:Lactic Acid / Q000378:metabolism* / Q000494:pharmacology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009474:Neurons / Q000187:drug effects / Q000378:metabolism* / Q000648:ultrastructure; D012333:RNA, Messenger / Q000378:metabolism; D017208:Rats, Wistar; D043562:Receptors, G-Protein-Coupled / Q000032:analysis / Q000378:metabolism*; D013569:Synapses / Q000378:metabolism; D009435:Synaptic Transmission
chemical_list: C529424:Hcar1 protein, mouse; D012333:RNA, Messenger; D043562:Receptors, G-Protein-Coupled; D019344:Lactic Acid; D000242:Cyclic AMP
keywords: astrocytic vascular end-feet; electron microscopy; excitatory synapses; lactate; volume transmitter