P2Y purinoceptor 2 and P2Y purinoceptor 4 (P2Y2 and P2Y4)

The P2Y2 and P2Y4 receptors are G protein-coupled receptors (GPCRs) belonging to the purinergic P2Y family, primarily activated by extracellular nucleotides such as ATP and UTP [1, 11]. These receptors are widely distributed in epithelial tissues, including the ocular surface and respiratory tract, where they regulate fluid and electrolyte transport by stimulating chloride secretion and inhibiting sodium absorption [4, 16]. In the eye, activation of P2Y2 and P2Y4 by agonists like diquafosol promotes the secretion of water, mucins, and lipids, making them effective targets for treating dry eye disease [3, 8]. In the lungs, P2Y2 agonists such as denufosol have been investigated for their ability to enhance mucociliary clearance in patients with cystic fibrosis [12, 23]. Beyond their role in secretion, P2Y2 and P2Y4 are involved in mediating inflammatory responses, wound healing, and cell proliferation [1, 18]. P2Y2 is often overexpressed in various cancers, including colon and pancreatic cancer, where it may contribute to tumor growth and metastasis [4, 15]. Consequently, P2Y2 and P2Y4 are also being explored as targets for antagonists to treat chronic inflammatory conditions, fibrosis, and neurodegenerative diseases like Alzheimer's [1, 18]. While generally well-tolerated when targeted topically, systemic or excessive activation of these receptors can lead to safety concerns such as respiratory irritation or the potential promotion of pathological inflammation [16, 18].

Other names

P2U purinoceptorP2U1P2URP2RU1P2Y2RATP receptorNRUP2PUNRP2Y4RPyrimidinergic receptor P2Y4Uridine nucleotide receptor

Agonism of P2Y2 and P2Y4 receptors stimulates Gq-protein-mediated activation of phospholipase C, leading to the release of intracellular calcium and the activation of chloride channels. This results in the secretion of water, mucin, and lipids from epithelial cells. Antagonism of these receptors inhibits signaling pathways involved in inflammation, fibrosis, and tumor cell proliferation.