NPY Y₅ receptor

NPY Y~5~ receptor (NPY5R) is a hypothalamic Y-type GPCR linked to neuropeptide Y-induced food intake, with Y~5~ mRNA detected mainly in the CNS and paraventricular hypothalamus^[1]. Mechanistically, human Y~5~ receptor signaling in HEC-1B cells is limited to inhibition of cAMP accumulation^[2]. In mouse models, Y~5~R contributes to feeding induced by centrally administered NPY and analogs, but is not a critical physiological feeding receptor alone^[3]. Compared with related isoforms, Y~1~ plays a dominant role in NPY-induced feeding, while Y~5~ functions as one feeding receptor within a redundant receptor network^[4]. In neuroblastoma models, NPY stimulates cell motility and invasiveness, and Y~5~R mediates RhoA activation, cytoskeleton remodeling, and cell movement^[5]. Y~5~R blockade also sensitized chemoresistant neuroblastoma cells to chemotherapy-induced apoptosis^[6]. For experimental applications, FMS586 provides a selective, orally active Y~5~ antagonist tool^[7]. However, MK-0557 showed that selective NPY5R antagonism did not induce clinically meaningful weight loss in overweight and obese adults^[8].