Hydroxycarboxylic acid receptor 3 (HCA3) (HCA3)

Hydroxycarboxylic acid receptor 3 (HCA3), also known as GPR109B, is a G protein-coupled receptor that is evolutionarily unique to humans and great apes [1, 2]. It is primarily expressed in adipocytes and various immune cells, including neutrophils and macrophages [1, 3]. HCA3 serves as a sensor for metabolic intermediates such as 3-hydroxyoctanoic acid and the bacterial metabolite D-phenyllactic acid, which is produced by lactic acid bacteria found in fermented foods [2]. Upon activation, HCA3 couples with Gi proteins to inhibit adenylyl cyclase, thereby reducing intracellular cAMP levels and modulating functions like lipolysis and immune cell chemotaxis [3, 4]. In the context of disease, HCA3 is involved in regulating inflammatory responses and has been investigated for its role in metabolic disorders and certain cancers [2, 3]. While niacin is a known exogenous ligand, its therapeutic utility is often limited by its higher affinity for the closely related HCA2 receptor, which mediates the characteristic flushing side effect [4].

Other names

HCAR3GPR109BHM74G protein-coupled receptor 109BNiacin receptor 2

Agonism of the HCA3 receptor activates Gi-type G proteins, leading to the inhibition of adenylyl cyclase activity and a subsequent decrease in intracellular cyclic AMP (cAMP) levels [3, 4].