GPR75: An exciting new target in metabolic syndrome and related disorders

Drug development advances in human genetics‐based targets

“…281,282 Reduction of 20-HETE-mediated hypertension, vascular dysfunction and vascular remodeling in the GPR75 KO animal model. 274,275 It suggests that knockdown of GPR75 prevents 20-HETE-mediated vascular remodeling and hypertension. In addition, GPR75 plays an important role in the pathogenesis of pulmonary hypertension and may attenuate cAMP-dependent signaling while enhancing lung contraction in response to hypoxia.…”

“…However, it is unique from other GPCRs in that it contains approximately 200 amino acids, a 92‐residue putative intracellular third loop, and an extra‐long C‐terminal tail of 169 residues 276 . GPR75 is primarily expressed in the brain and central nervous system 275 . In addition, it is expressed at low levels in alternate tissues including the heart and kidney 274 …”

“…GPR75 is the first specific receptor for 20‐hydroxyeicosatetraenoic acid (20‐HETE), and studies have shown that 20‐HETE signals through GPR75 to influence vascular function 281,282 . Reduction of 20‐HETE‐mediated hypertension, vascular dysfunction and vascular remodeling in the GPR75 KO animal model 274,275 . It suggests that knockdown of GPR75 prevents 20‐HETE‐mediated vascular remodeling and hypertension.…”

“…In conclusion, GPR75 is a potentially biologically and pharmacologically significant receptor that plays a crucial role in many diseases such as obesity, cancer and metabolic syndrome. Inhibition of GPR75's may have beneficial effects on diverse diseases including cerebrovascular disease, cardiovascular disease, diabetes, cancer, and obesity 275,286 …”

Activation of GPR75 Signaling Pathway Contributes to the Effect of a 20-HETE Mimetic, 5,14-HEDGE, to Prevent Hypotensive and Tachycardic Responses to Lipopolysaccharide in a Rat Model of Septic Shock

“…20 As prominent therapeutic drug targets, G protein-coupled receptors (GPRs) are a large family of mammalian 7-transmembrane proteins expressed in numerous tissues and frequently interact with particular Ga protein members. [21][22][23] GPR75, one of the orphan GPRs, has been reported to be expressed in endothelial, aortic, and cerebral vascular smooth muscle cells (VSMCs), 2,24 kidney, 25 brain, 25,26 spleen, 25 lung, 25 liver, 25 skeletal muscle, 25 and testis 25 tissues of rats and/or mouse as well as mouse and human islets. 27 Considering these studies, little is known about the expression and cellular distribution of GPR75 in the vasculature.…”