HCAR1

Hydroxycarboxylic acid receptor 1 (HCAR1), also known as GPR81, is a G-protein-coupled receptor activated primarily by L-lactate, mediating metabolic sensing and neuroprotective signaling in the central nervous system^[1][2][3]. Mechanistically, HCAR1 modulates Gα_i/o and Gα_s pathways without recruiting β-arrestins, linking lactate levels to downstream regulation of cAMP and gene expression in astrocytes and neurons^[4][5]. In experimental models, HCAR1 activation promotes axonal development and protects unmyelinated axons and myelin under hypoglycemic conditions, highlighting its role in neural energy homeostasis^[6]. Functionally, HCAR1 contributes to epileptic seizure modulation by controlling neuronal excitability, as HCAR1-deficient mice exhibit increased seizure severity and lowered thresholds^[7]. In oncology, HCAR1 enhances chemoresistance and survival in cervical cancer cells through up-regulation of ABCB1 transporter and DNA repair proteins, indicating its impact on tumor metabolism and therapy resistance^[8][9]. Compared with other hydroxycarboxylic acid receptor isoforms, HCAR1 exhibits a compact ligand-binding pocket stabilized by unique disulfide bonds, conferring selective recognition for lactate versus structurally related metabolites^[5]. For experimental applications, selective agonists such as CHBA and AZ7136 and allosteric modulators have been developed, allowing precise probing of HCAR1-mediated pathways in metabolic, neurological, and cancer models^[5][4]. These pharmacological tools support both mechanistic studies and the design of interventions targeting metabolic signaling and neuroprotection.