The P2Y2 receptor is a protein on the surface of cells that belongs to the purinergic receptor family, which responds to molecules like adenosine triphosphate (ATP). While known for its role in cellular energy, ATP also acts as an external signal. The P2Y2 receptor is activated by both ATP and another molecule, uridine triphosphate (UTP).
This dual activation makes it responsive to signals present during tissue stress or injury when these molecules are released. As a G protein-coupled receptor (GPCR), P2Y2 translates these external chemical signals into internal cellular actions, influencing a wide variety of biological functions.
The P2Y2 Signaling Mechanism
When ATP or UTP binds to the P2Y2 receptor, the receptor protein changes its three-dimensional shape. This change allows it to interact with and activate a G-protein on the inner cell membrane. The P2Y2 receptor specifically couples with a G-protein from the Gq family.
Once activated, this Gq protein turns on a nearby enzyme called Phospholipase C (PLC). PLC’s function is to cleave a lipid molecule in the cell membrane, generating two smaller molecules that act as secondary messengers: inositol 1,4,5-trisphosphate (IP3) and diacylglycerol (DAG). These messengers amplify the initial signal.
The IP3 molecule travels to the endoplasmic reticulum, which serves as a storage site for calcium ions. IP3 binds to receptors on this compartment, causing channels to open and release a surge of stored calcium into the cell. This increase in intracellular calcium concentration triggers various cellular actions, from secretion to muscle contraction.
Physiological Roles of P2Y2
In the respiratory system, P2Y2 receptor activation helps regulate airway hydration and mucus clearance. When activated on airway cells, it stimulates the secretion of ions and, consequently, water. This process keeps the mucus layer thin, allowing the cilia—tiny hair-like structures—to effectively clear trapped particles and pathogens from the lungs.
Within the immune system, the receptor initiates a protective response to tissue damage. When cells are injured, they release ATP, which acts as a “find-me” signal. This ATP activates P2Y2 receptors on immune cells like macrophages, guiding them to the site of injury or infection as a fundamental part of the body’s repair mechanisms.
P2Y2 signaling also helps regulate blood vessel tone and blood pressure. Activation of these receptors on the endothelial cells that line blood vessels leads to the production of nitric oxide, a molecule that causes the surrounding smooth muscle to relax. This vasodilation, or widening of the blood vessels, helps to lower blood pressure.
On the surface of the eye, the P2Y2 receptor is responsible for the production and stability of the tear film. By stimulating the secretion of water and mucins from cells in the conjunctiva, it contributes to a healthy tear layer. This function is necessary for lubricating the ocular surface and ensuring clear vision.
Involvement in Disease Processes
While P2Y2 receptor activation is beneficial for acute immune responses, its persistent activation can contribute to chronic inflammatory conditions. The mechanism that summons immune cells to an injury becomes detrimental if constantly triggered, leading to sustained inflammation in diseases like inflammatory bowel disease. In these states, the continuous presence of ATP keeps the inflammatory cycle active through the P2Y2 receptor.
Research has implicated the P2Y2 receptor in cancer progression and metastasis. Some tumor cells overexpress this receptor, and the ATP-rich environment of a tumor can be exploited to fuel cancer cell growth and spread. Activation of P2Y2 can promote cell invasion and migration for cancers such as breast and prostate cancer.
In the context of cystic fibrosis (CF), the P2Y2 receptor has been a subject of research. CF is caused by mutations in the CFTR gene, which disrupts a chloride channel in epithelial cells, leading to thick, dehydrated mucus in the airways. Because P2Y2 activation provides an alternative pathway for ion and fluid transport, it has been explored as a way to bypass the defective CFTR channel and restore hydration.
The receptor’s role in ocular hydration directly links it to dry eye disease. Insufficient function of P2Y2 can lead to a deficient and unstable tear film, causing symptoms of dryness and irritation. The pathology can involve a cycle where surface damage and inflammation further impair the mechanisms that rely on P2Y2 for proper tear secretion.
P2Y2 as a Therapeutic Target
Given its role in tear production, the P2Y2 receptor has become a target for drugs to treat dry eye disease. These drugs, known as agonists, work by activating the receptor. A primary example is Diquafosol, a P2Y2 agonist used in ophthalmic solutions. When administered as an eye drop, Diquafosol stimulates P2Y2 receptors on the conjunctiva, promoting the secretion of water and mucin to improve the tear film.
Conversely, drugs that block the P2Y2 receptor, known as antagonists, are under investigation for conditions where its activity is detrimental. P2Y2 antagonists have shown potential for treating chronic inflammatory diseases by preventing the receptor from being continuously activated by ATP. This approach could dampen the persistent immune response that drives these disorders.
The development of P2Y2 antagonists is also a focus of cancer research. By blocking the receptor on cancer cells, these drugs could inhibit tumor growth and metastasis fueled by ATP in the tumor microenvironment. Research suggests that inhibiting P2Y2 signaling could interfere with cancer cell proliferation and invasion, offering a potential new strategy for treatment.