The Lactate Receptor HCAR1 Modulates Neuronal Network Activity through the Activation of G<sub>α</sub> and G<sub>βγ</sub> Subunits.

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Serval ID
serval:BIB_A7DD5C903273
Type
Article: article from journal or magazin.
Collection
Publications
Institution
Title
The Lactate Receptor HCAR1 Modulates Neuronal Network Activity through the Activation of G<sub>α</sub> and G<sub>βγ</sub> Subunits.
Journal
The Journal of neuroscience
Author(s)
de Castro Abrantes H., Briquet M., Schmuziger C., Restivo L., Puyal J., Rosenberg N., Rocher A.B., Offermanns S., Chatton J.Y.
ISSN
1529-2401 (Electronic)
ISSN-L
0270-6474
Publication state
Published
Issued date
05/06/2019
Peer-reviewed
Oui
Volume
39
Number
23
Pages
4422-4433
Language
english
Notes
Publication types: Journal Article ; Research Support, Non-U.S. Gov't
Publication Status: ppublish
Abstract
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 <sub>iα</sub> -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 <sub>B</sub> , and α <sub>2A</sub> -adrenergic receptors, through a mechanism involving both its G <sub>iα</sub> and G <sub>iβγ</sub> 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 <sub>iα</sub> and G <sub>iβγ</sub> intracellular pathways to functionally interact with other G <sub>i</sub> -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 <sub>B</sub> , adenosine A1- and α <sub>2A</sub> -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.
Keywords
Action Potentials, Animals, Calcium Signaling/drug effects, Cells, Cultured, Cerebral Cortex/cytology, Cyclic AMP/physiology, Excitatory Postsynaptic Potentials/drug effects, Excitatory Postsynaptic Potentials/physiology, Female, Heterotrimeric GTP-Binding Proteins/physiology, Lactates/metabolism, Male, Mice, 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, Primary Cell Culture, 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, GPR81, HCAR1, intracellular pathway, lactate, neurons, spontaneous activity
Pubmed
Web of science
Research datasets
Open Access
Yes
Funding(s)
Swiss National Science Foundation / Projects / 31003A_179399
Create date
02/04/2019 7:33
Last modification date
07/07/2020 5:20
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