Journal
JOURNAL OF NEUROSCIENCE
Volume 39, Issue 23, Pages 4422-4433Publisher
SOC NEUROSCIENCE
DOI: 10.1523/JNEUROSCI.2092-18.2019
Keywords
GPR81; HCAR1; intracellular pathway; lactate; neurons; spontaneous activity
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Funding
- Swiss National Science Foundation [31003A_179399]
- Swiss National Science Foundation (SNF) [31003A_179399] Funding Source: Swiss National Science Foundation (SNF)
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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(i alpha)-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 alpha(2A)-adrenergic receptors, through a mechanism involving both its G(i alpha) and G(i beta gamma) 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(i alpha) and G(i beta gamma) intracellular pathways to functionally interact with other G(i)-coupled receptors for the fine tuning of neuronal activity.
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