The Lactate Receptor HCAR1 Modulates Neuronal Network Activity through the Activation of Gα and Gβγ Subunits
| Autor: | Nadia Rosenberg, Jean-Yves Chatton, Céline Schmuziger, Haissa de Castro Abrantes, Julien Puyal, Leonardo Restivo, Stefan Offermanns, Anne-Bérengère Rocher, Marc Briquet |
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| Jazyk: | angličtina |
| Rok vydání: | 2019 |
| Předmět: |
0301 basic medicine
Male Primary Cell Culture Action Potentials Nerve Tissue Proteins GPR81 Second Messenger Systems Receptors G-Protein-Coupled 03 medical and health sciences Mice 0302 clinical medicine Calcium imaging medicine Biological neural network Cyclic AMP Premovement neuronal activity Animals Patch clamp Calcium Signaling Receptor Research Articles Cells Cultured G protein-coupled receptor Calcium Signaling/drug effects Cerebral Cortex/cytology Cyclic AMP/physiology Excitatory Postsynaptic Potentials/drug effects Excitatory Postsynaptic Potentials/physiology Female Heterotrimeric GTP-Binding Proteins/physiology Lactates/metabolism Mice Inbred C57BL Mice Knockout Miniature Postsynaptic Potentials/drug effects Miniature Postsynaptic Potentials/physiology Nerve Tissue Proteins/agonists Nerve Tissue Proteins/deficiency Nerve Tissue Proteins/genetics Nerve Tissue Proteins/physiology Neurons/drug effects Neurons/physiology Receptors G-Protein-Coupled/agonists Receptors G-Protein-Coupled/deficiency Receptors G-Protein-Coupled/genetics Receptors G-Protein-Coupled/physiology Second Messenger Systems/drug effects HCAR1 intracellular pathway lactate neurons spontaneous activity Cerebral Cortex Neurons Chemistry General Neuroscience Miniature Postsynaptic Potentials Excitatory Postsynaptic Potentials Heterotrimeric GTP-Binding Proteins Cell biology 030104 developmental biology Mechanism of action nervous system Lactates medicine.symptom 030217 neurology & neurosurgery |
| Zdroj: | The Journal of neuroscience, vol. 39, no. 23, pp. 4422-4433 |
| Popis: | The discovery of a G-protein-coupled receptor for lactate named hydroxycarboxylic acid receptor 1 (HCAR1) in neurons has pointed to additional nonmetabolic effects of lactate for regulating neuronal network activity. In this study, we characterized the intracellular pathways engaged by HCAR1 activation, using mouse primary cortical neurons from wild-type (WT) and HCAR1 knock-out (KO) mice from both sexes. Using whole-cell patch clamp, we found that the activation of HCAR1 with 3-chloro-5-hydroxybenzoic acid (3Cl-HBA) decreased miniature EPSC frequency, increased paired-pulse ratio, decreased firing frequency, and modulated membrane intrinsic properties. Using fast calcium imaging, we show that HCAR1 agonists 3,5-dihydroxybenzoic acid, 3Cl-HBA, and lactate decreased by 40% spontaneous calcium spiking activity of primary cortical neurons from WT but not from HCAR1 KO mice. Notably, in neurons lacking HCAR1, the basal activity was increased compared with WT. HCAR1 mediates its effect in neurons through a G iα -protein. We observed that the adenylyl cyclase-cAMP-protein kinase A axis is involved in HCAR1 downmodulation of neuronal activity. We found that HCAR1 interacts with adenosine A1, GABA B , and α 2A -adrenergic receptors, through a mechanism involving both its G iα and G iβγ subunits, resulting in a complex modulation of neuronal network activity. We conclude that HCAR1 activation in neurons causes a downmodulation of neuronal activity through presynaptic mechanisms and by reducing neuronal excitability. HCAR1 activation engages both G iα and G iβγ intracellular pathways to functionally interact with other G i -coupled receptors for the fine tuning of neuronal activity.SIGNIFICANCE STATEMENT Expression of the lactate receptor hydroxycarboxylic acid receptor 1 (HCAR1) was recently described in neurons. Here, we describe the physiological role of this G-protein-coupled receptor (GPCR) and its activation in neurons, providing information on its expression and mechanism of action. We dissected out the intracellular pathway through which HCAR1 activation tunes down neuronal network activity. For the first time, we provide evidence for the functional cross talk of HCAR1 with other GPCRs, such as GABA B , adenosine A1- and α 2A -adrenergic receptors. These results set HCAR1 as a new player for the regulation of neuronal network activity acting in concert with other established receptors. Thus, HCAR1 represents a novel therapeutic target for pathologies characterized by network hyperexcitability dysfunction, such as epilepsy. |
| Databáze: | OpenAIRE |
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