Lactate enhances Arc/arg3.1 expression through hydroxycarboxylic acid receptor 1-β-arrestin2 pathway in astrocytes

Abstract In recent years, with the discovery and research of lactate-specific receptor HCAR1(hydroxycarboxylic acid receptor 1), lactate is not only as a product of Glycolysis in astrocytes, but also as a signaling molecule which has gradually received attention. Studies have found that lactate can be used as an intercellular signaling molecule involved in synaptic plasticity, and so that peripheral administration of lactate can produce antidepressant effects. Here, we focus on HCAR1 on the most widely distributed astrocytes in the brain, found and verified that lactate could cause Arc/arg3.1 protein overexpression in astrocytes through HCAR1. However, the expression of Arc/arg3.1 does not depend on the Gi protein pathway of HCAR1, and we found that lactate enhanced the expression of Arc/arg3.1 protein through the HCAR1-β-arrestin2 pathway. In summary, lactate acts on HCAR1 of astrocytes. It enhances the expression of MAPK-dependent Arc through β-arrestin2, thereby reducing the influx of calcium ions when astrocytes are exposed to glutamate damage, achieving the role of protecting astrocytes and indirectly enhancing the absorption of glutamate by astrocytes. These results also demonstrate that HCAR1 in the brain is a potential therapeutic target in an experimental in vitro model of glutamate damage, which is strongly associated with many neurodegenerative diseases.