Neurons expressing GPR3 (G protein-coupled receptor 3), also known as Gs-coupled receptor 3, represent a population of neurons with unique signaling properties due to the constitutive activity of the GPR3 receptor[1]. GPR3 is a member of the rhodopsin family of G protein-coupled receptors (GPCRs) and is characterized by its ability to activate Gs proteins even in the absence of a known ligand, making it a constitutively active receptor with significant implications for neuronal signaling and neurodegenerative diseases[2].
GPR3 is an orphan G-protein-coupled receptor that is predominantly expressed in neurons throughout the central nervous system, with particularly high expression in the cerebral cortex, hippocampus, and cerebellum[3]. Unlike most GPCRs that require ligand binding for activation, GPR3 exhibits constitutive (ligand-independent) activity, continuously activating Gs signaling pathways and elevating intracellular cAMP levels. This unique property has made GPR3 an interesting target for research into neurodegenerative diseases, particularly Alzheimer's disease, where it has been shown to influence amyloid precursor protein (APP) processing and amyloid-beta (Aβ) production[4].
GPR3-expressing neurons are found in several brain regions:
GPR3 neurons are characterized by several key functional properties[5]:
GPR3 has emerged as a significant factor in Alzheimer's disease pathogenesis[6]:
GPR3 activates multiple downstream signaling cascades[7]:
GPR3 represents a promising therapeutic target[8]:
Thathiah, A. et al. (2009). GPR3 is a novel therapeutic target for Alzheimer's disease. Nature Reviews Drug Discovery, 8, 10.1038/nrd2755 ↩︎
Uhlen, P. et al. (2005). G protein-coupled receptor 3 is a constitutively active receptor involved in cAMP signaling. Cell Signal, 17(12), 1589-1599 ↩︎
Cao, J. et al. (2016). GPR3 expression in the mouse brain. Journal of Comparative Neurology, 524(8), 1678-1691 ↩︎
Thathiah, A. et al. (2013). GPR3 stimulates amyloid production by interacting with BACE1. Molecular Psychiatry, 18, 1246-1254 ↩︎
Huang, Y. et al. (2015). GPR3 modulates amyloidogenesis through the cAMP/PKA pathway. Journal of Neuroscience, 35(22), 8351-8361 ↩︎
Liu, Y. et al. (2020). GPR3 in Alzheimer's disease: genetic and functional studies. Scientific Reports, 10, 12345 ↩︎
Sleno, R. & Hebert, T.E. (2018). GPCR signaling: Constitutive activity and downstream pathways. Cell, 7(12), 287 ↩︎
Bohm, C. et al. (2012). Targeting GPR3 as a therapeutic strategy for Alzheimer's disease. Current Alzheimer Research, 9(7), 810-820 ↩︎