Ligand Recognition and Hydroxy-Carboxylic Acid Receptor 2 SignalingModulation: A Structural Analysis

Hydroxycarboxylic acid receptors (HCAR1, HCAR2, and HCAR3) belong to the family of G protein-coupled receptors (GPCRs) which are involved in transducing Gi/o signaling upon treatment with certain ligands, such as lactic acid, butyric acid, or 3-hydroxyoctanoic acid.These metabolites are relevant to numerous pathophysiological processes including lipolysis, atherogenesis, and neuroinflammatory responses.Among these, HCAR2 has excited the interest of clinical research and practice owing to its wider therapeutic applications.Endogenous ligands like -hydroxybutyrate (3-HB) and butyrate that bind and activate HCAR2 have been reported to modulate fat metabolism and immune activities promoting its exploitation in the management of cardiovascular conditions as well as neuroinflammatory diseases like multiple sclerosis and Parkinson disease.Apart from that HCAR2 has been linked with its engagement with niacin (vitamin B3) leading to its use in the treatment of dyslipidemia which is a predominant risk factor for cardiovascular disease.This review highlights examples of recent structural studies of HCARs using cryo-EM examining the molecular details relevant to HCAR signaling and how these receptors are activated.Exposing the structural elements of HCAR allows determining the features of the receptors responsible for their functions in health and disease opening new prospects for therapeutic development for metabolic and neuroinflammatory disorders.