GPR81

GPR81, also known as hydroxycarboxylic acid receptor 1 (HCAR1), is a G protein–coupled receptor activated by the metabolite L-lactate. It predominantly couples to Gi/o proteins, leading to inhibition of adenylyl cyclase and a decrease in intracellular cyclic AMP, which can influence cellular metabolism and signaling.

Expression of GPR81 is reported in adipose tissue, where it mediates lactate’s antilipolytic effect; it is also found in certain brain cells, including neurons and glial cells, and in various immune cell populations such as dendritic cells and macrophages. This distribution supports roles in energy homeostasis, brain function, and immune regulation.

Physiological roles of GPR81 center on lactate signaling. In adipose tissue, receptor activation suppresses lipolysis by lowering cAMP levels and reducing hormone-sensitive lipase activity, providing feedback on lipid mobilization in response to changes in glycolytic activity, such as during exercise. In the brain, lactate signaling through GPR81 is thought to modulate neuronal excitability and may influence cerebral blood flow, though the exact mechanisms remain under investigation. In the immune system, lactate-GPR81 signaling has been reported to dampen dendritic cell activation and inflammatory responses, a process that can contribute to the immunosuppressive environment observed in some tumor contexts.

Clinical and research significance: Because lactate rises in metabolic stress and within the tumor microenvironment, GPR81 is of interest as a potential target in metabolic diseases and cancer immunology. Pharmacological modulation of GPR81 could affect lipolysis, energy balance, and immune function, but tissue-specific effects and safety require thorough investigation.