Versatile lactate signaling via HCAR1: a multifaceted GPCR involved in many biological processes

Abstract

G-coupled protein receptors (GPCRs) are the ultimate refuge of pharmacology and medicine as more than 40% of all marketed drugs are directly targeting these receptors. Through cell surface expression, they are at the forefront of cellular communication with the outside world. Metabolites among the conveyors of this communication are becoming more prominent with the recognition of them as ligands for GPCRs. HCAR1 is a GPCR conveyor of lactate. It is a class A GPCR coupled to G_αi which reduces cellular cAMP along with the downstream G_βγ signaling. It was first found to inhibit lipolysis, and lately has been implicated in diverse cellular processes, including neural activities, angiogenesis, inflammation, vision, cardiovascular function, stem cell proliferation, and involved in promoting pathogenesis for different conditions, such as cancer. Other than signaling from the plasma membrane, HCAR1 shows nuclear localization with different location-biased activities therein. Although different functions for HCAR1 are being discovered, its cell and molecular mechanisms are yet ill understood. Here, we provide a comprehensive review on HCAR1, which covers the literature on the subject, and discusses its importance and relevance in various biological phenomena.

Keywords: GPCR; HCAR1; lactate; location bias; location-biased signaling; signal transduction.