2. Academic Validation
  3. History and Function of the Lactate Receptor GPR81/HCAR1 in the Brain: A Putative Therapeutic Target for the Treatment of Cerebral Ischemia

History and Function of the Lactate Receptor GPR81/HCAR1 in the Brain: A Putative Therapeutic Target for the Treatment of Cerebral Ischemia

  • Neuroscience. 2023 Aug 21:526:144-163. doi: 10.1016/j.neuroscience.2023.06.022.
Anna Clara Machado Colucci 1,  Isadora D'Ávila Tassinari 1,  Eloísa da Silveira Loss 2,  Luciano Stürmer de Fraga 3
Affiliations

Affiliations

  • 1 Laboratório de Neurobiologia e Metabolismo (NeuroMet), Departamento de Fisiologia, Instituto de Ciências Básicas da Saúde (ICBS), Universidade Federal do Rio Grande do Sul (UFRGS), Rua Ramiro Barcelos, 2600, lab. 660, Porto Alegre, Brazil; Programa de Pós-Graduação em Ciências Biológicas: Fisiologia, Instituto de Ciências Básicas da Saúde (ICBS), Universidade Federal do Rio Grande do Sul (UFRGS), Rua Ramiro Barcelos, 2600, Porto Alegre, Brazil; Centro de Pesquisa Experimental, Hospital de Clínicas de Porto Alegre (HCPA), Rua Ramiro Barcelos, 2350, Porto Alegre, Brazil.
  • 2 Laboratório de Endocrinologia Experimental (LABENEX), Departamento de Fisiologia, Instituto de Ciências Básicas da Saúde (ICBS), Universidade Federal do Rio Grande do Sul (UFRGS), Rua Ramiro Barcelos, 2600, lab. 660, Porto Alegre, Brazil; Programa de Pós-Graduação em Ciências Biológicas: Fisiologia, Instituto de Ciências Básicas da Saúde (ICBS), Universidade Federal do Rio Grande do Sul (UFRGS), Rua Ramiro Barcelos, 2600, Porto Alegre, Brazil.
  • 3 Laboratório de Neurobiologia e Metabolismo (NeuroMet), Departamento de Fisiologia, Instituto de Ciências Básicas da Saúde (ICBS), Universidade Federal do Rio Grande do Sul (UFRGS), Rua Ramiro Barcelos, 2600, lab. 660, Porto Alegre, Brazil; Programa de Pós-Graduação em Ciências Biológicas: Fisiologia, Instituto de Ciências Básicas da Saúde (ICBS), Universidade Federal do Rio Grande do Sul (UFRGS), Rua Ramiro Barcelos, 2600, Porto Alegre, Brazil; Centro de Pesquisa Experimental, Hospital de Clínicas de Porto Alegre (HCPA), Rua Ramiro Barcelos, 2350, Porto Alegre, Brazil. Electronic address: [email protected].
PMID: 37391123 DOI: 10.1016/j.neuroscience.2023.06.022
Abstract

GPR81 is a G-protein coupled receptor (GPCR) discovered in 2001, but deorphanized only 7 years later, when its affinity for lactate as an endogenous ligand was demonstrated. More recently, GPR81 expression and distribution in the brain were also confirmed and the function of lactate as a volume transmitter has been suggested since then. These findings shed light on a new function of lactate acting as a signaling molecule in the central nervous system, in addition to its well-known role as a metabolic fuel for neurons. GPR81 seems to act as a metabolic sensor, coupling energy metabolism, synaptic activity, and blood flow. Activation of this receptor leads to Gi-mediated downregulation of adenylyl cyclase and subsequent reduction in cAMP levels, regulating several downstream pathways. Recent studies have also suggested the potential role of lactate as a neuroprotective agent, mainly under brain ischemic conditions. This effect is usually attributed to the metabolic role of lactate, but the underlying mechanisms need further investigation and could be related to lactate signaling via GPR81. The activation of GPR81 showed promising results for neuroprotection: it modulates many processes involved in the pathophysiology of ischemia. In this review, we summarize the history of GPR81, starting with its deorphanization; then, we discuss GPR81 expression and distribution, signaling transduction cascades, and neuroprotective roles. Lastly, we propose GPR81 as a potential target for the treatment of cerebral ischemia.

Keywords

GPR81; HCAR1; L-lactate; cerebral ischemia; neuroprotection.

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