P2Y2R

Dopamine (DA) is a well-studied neurochemical in the mammalian carotid body (CB), a chemosensory organ involved in O2 and CO2 /H+ homeostasis. DA released from receptor (type I) cells during chemostimulation is predominantly inhibitory, acting via pre- and post-synaptic dopamine D2 receptors (D2R) on type I cells and afferent (petrosal) terminals respectively. By contrast, co-released ATP is excitatory at postsynaptic P2X2/3R, though paracrine P2Y2R activation of neighboring glial-like type II cells may boost further ATP release...

Osteoblasts release adenosine triphosphate (ATP) out of the cell following mechanical stress. Although it is well established that extracellular ATP affects bone metabolism via P2 receptors [such as purinergic receptor P2X7 (P2X7R) and purinergic receptor P2Y2 (P2Y2R)], the mechanism of ATP release from osteoblasts remains unknown. Recently, a vesicular nucleotide transporter [VNUT, solute carrier family 17 member 9 (SLC17A9)] that preserves ATP in vesicles has been identified. The purpose of this study was to elucidate the role of VNUT in osteoblast bone metabolism...

Inflammatory and wound healing responses take place during liver damage, primarily in the parenchymal tissue. It is known that cellular injury elicits an activation of the purinergic signaling, mainly by the P2X7 receptor; however, the role of P2Y receptors in the onset of liver pathology such as fibrosis has not been explored. Hence, we used mice treated with the hepatotoxin CCl4 to implement a reversible model of liver fibrosis to evaluate the expression and function of the P2Y2 receptor (P2Y2R). Fibrotic livers showed an enhanced expression of P2Y2R that eliminated its zonal distribution...

The improvement of cryopreserved oocyte survival is imperative for the preservation of female fertility. In this study, we investigate whether P2Y2 receptors (P2Y2R) can be directly implicated in calcium (Ca2+ ) homeostasis misbalances observed during the cryopreservation process of cumulus oocyte complexes (COC). Firstly, RNA was extracted from bovine immature and mature oocytes and cumulus cells and real-time PCR performed to identify P2Y2R transcripts (experiment 1). Changes in intracellular calcium concentration [Ca2+]i of mature COC and oocytes (experiment 2) were measured upon exposure to cryoprotectants (CPA), UTP (P2Y2R stimulator, 100 μM), and/or suramin (P2Y2R inhibitor, 100 and 300 μM)...

Release of ATP to the extracellular compartment and subsequent activation of purinergic receptors is a conserved mechanism mediating inflammatory responses and cell fate decisions in various organs including the liver. Previous findings suggest that extracellular ATP may promote liver tumorigenesis, however, the underlying mechanisms are poorly understood. Therefore, our aim was to dissect the functions of extracellular ATP and P2Y2 receptors (P2Y2 R) during hepatocarcinogenesis. Liver tumors were induced in wild-type and P2y2 r -/- knockout mice by intraperitoneal diethylnitrosamine (DEN) injection...

Extracellular adenosine triphosphate (eATP)-driven inflammation was observed in chronic obstructive pulmonary disease (COPD) but was not investigated in patients' blood. Therefore, this study aimed to investigate eATP concentration in plasma of COPD patients and its association with disease severity and smoking. Study included 137 patients with stable COPD and 95 control subjects. eATP concentration was determined in EDTA plasma by luminometric method, and mRNA expression of eATP receptors P2X7R and P2Y2R was analysed by quantitative polymerase chain reaction (qPCR)...

Inflammation plays a central role in the progression of alcoholic liver disease. ATP-P2Y2R signaling and CD39 play an important role in various diseases, but little is known about their role in alcoholic liver steatosis and inflammation. As a transmembrane hydrolase, CD39 hydrolyzes ATP, while the mutual regulation of CD39 and ATP-P2Y2R in alcoholic steatohepatitis is poorly understood. Here, we found that the expression of ATP, P2Y2R, and CD39 is increased significantly both in the liver of alcohol-fed mice and alcohol-induced RAW264...

Caveolae-associated protein caveolin-1 (Cav-1) plays key roles in cellular processes such as mechanosensing, receptor coupling to signaling pathways, cell growth, apoptosis, and cancer. In 1321N1 astrocytoma cells Cav-1 interacts with the P2Y2 receptor (P2Y2 R) to modulate its downstream signaling. P2Y2 R and its signaling machinery also mediate pro-survival actions after mechanical injury. This study determines if Cav-1 knockdown (KD) affects P2Y2 R signaling and its pro-survival actions in the 1321N1 astrocytoma cells mechanical injury model system...

Magnocellular neurons in the supraoptic nucleus (SON), which synthesize and release arginine vasopressin (AVP) and oxytocin (OT), express several subtypes of ATP-stimulated purinergic P2X receptors (P2XR) that modulate neuronal activity as well as neurotransmitter and hormone release. However, the physiological impact of this modulation is not well understood. Here, we tested a hypothesis that P2XRs play a role in the sustained release of hormones from SON neurons stimulated through fasting/refeeding. We studied the effect of 2 h of refeeding after 48 h of fasting on P2XR and P2YR mRNA expression and ATP-induced presynaptic and postsynaptic responses in the SON of 30-day-old rats...

Extracellular purines through specific receptors have been recognized as new regulators of ovarian function. It is known that P2Y2 receptor activity induces theca cell proliferation, we hypothesized that purinergic signaling controls the changes related with hyperthecosis in polycystic ovarian syndrome (PCOS). The aim of this study was to analyze the expression of UTP-sensitive P2Y receptors and their role in theca cells (TC) proliferation in experimentally-induced PCOS (EI-PCOS). In primary cultures of TC from intact rats, all the transcripts of P2Y receptors were detected by PCR; in these cells UTP (10 μM) induced extracellular signal-regulated kinases (ERK) phosphorylation...

NEW FINDINGS: What is the central question of this study? The mammalian carotid body (CB) is a peripheral chemoreceptor organ involved in O2 and CO2 /H+ homeostasis. Recent studies suggest that 5-HT, released from CB receptor cells, can stimulate adjacent glial-like type II cells, leading to an increase in intracellular Ca2+ (Δ[Ca2+ ]i ) and activation of ATP-permeable pannexin-1 (Panx-1) channels. The aim of this study was to elucidate the role of protein kinases in the 5-HT-[Ca2+ ]i -Panx-1 signalling pathway...

In the tumor microenvironment, extracellular nucleotides are released and accumulate, and can activate the P2Y2 receptor (P2Y2R), which regulates various responses in tumor cells, resulting in tumor progression and metastasis. Moreover, the inflammasome has recently been reported to be associated with tumor progression. However, the role of P2Y2R in inflammasome activation in breast cancer cells is not yet well defined. Therefore, in this study, we investigated the role of P2Y2R in inflammasome-mediated tumor progression in breast cancer using breast cancer cells and radiotherapy-resistant (RT‑R) breast cancer cells...

Endogenously released adenosine-5'-triphosphate (ATP) is a key regulator of physiological function and inflammatory responses in the kidney. Genetic or pharmacological inhibition of purinergic receptors has been linked to attenuation of inflammatory disorders and hence constitutes promising new avenues for halting and reverting inflammatory renal diseases. However, the involvement of purinergic receptors in glomerulonephritis (GN) has only been incompletely mapped. Here, we demonstrate that induction of GN in an experimental antibody-mediated GN model results in a significant increase of urinary ATP-levels and an upregulation of P2Y2R expression in resident kidney cells as well as infiltrating leukocytes pointing toward a possible role of the ATP/P2Y2R-axis in glomerular disease initiation...

The circadian rhythms in physiological and behavioral functions are driven by a pacemaker located in the suprachiasmatic nucleus (SCN). The rhythms continue in constant darkness and depend on cell-cell communication between neurons and glia. The SCN astrocytes generate also a circadian rhythm in extracellular adenosine 5'-triphosphate (ATP) accumulation, but molecular mechanisms that regulate ATP release are poorly understood. Here, we tested the hypothesis that ATP is released via the plasma membrane purinergic P2X7 receptors (P2X7Rs) and P2Y receptors (P2YRs) which have been previously shown to be expressed in the SCN tissue at transcriptional level...

G-protein-coupled P2Y receptors activated by extracellular nucleotides play important roles under different physiological and pathophysiological conditions in mammals. To investigate the immunological relevance of P2Y receptors in fish, we identified and characterized the P2Y2 and P2Y12 receptors in Japanese flounder Paralichthys olivaceus. The P. olivaceus P2Y2 and P2Y12 receptors harbor seven transmembrane domains but share only 24% sequence identity. Real-time PCR analysis revealed the constitutive but unequal mRNA expression pattern of P2Y2 R and P2Y12 R in normal Japanese flounder tissues with the dominant expression of P2Y2 R in head kidney and blood and P2Y12 R in hepatopancreas...

The disturbances of cellular proteostasis caused by the alteration in the ubiquitin-proteasome system (UPS) have been proposed as a common mechanism underlying several neural pathologies that involve a neuroinflammatory process. As we have previously reported that the nucleotide receptor P2Y purinoceptor 2 (P2Y2 R) regulates the proteasomal catalytic activities, we wonder whether this receptor is involved in the UPS disturbances associated with the neuroinflammation process. With the use of mice expressing a UPS reporter [mice expressing the UPS reporter ubiquitinG76V -green fluorescent protein (UbGFP mice)], we found that LPS-induced acute neuroinflammation status causes a UPS impairment in astrocytes and microglial cells by a mechanism dependent on P2Y2 R...

Many class C G-protein coupled receptors (GPCRs) function as homo- or heterodimers and several class A GPCRs have also been shown to form a homodimer. We expressed human P2Y2 receptor (P2Y2R) in cultured cells and compared SDS-PAGE patterns under reducing and non-reducing conditions. Under non-reducing conditions, approximately half of the P2Y2Rs were electrophoresed as a dimer. We then produced Cys to Ser mutants at four sites (Cys25, Cys106, Cys183 and Cys278) in the extracellular domains of P2Y2R and examined the effect on dimer formation and receptor activity...

Purinergic receptors are implicated in the pathogenesis of gastrointestinal disorders and are being explored as potential therapeutic targets. Gut inflammation releases ATP that acts on neuronal, glial, epithelial and immune cells. Purinergic signalling in glia and neurons is implicated in enteric neuropathies. Inflammation activates glia to increase ATP release and alter purinergic signalling. ATP release causes neuron death and gut motor dysfunction in colitis via a P2X7-dependent neural-glial pathway and a glial purinergic-connexin-43 pathway...

The G protein-coupled P2Y2 receptor, activated by ATP and UTP has been reported as a potential drug target for a wide range of important clinical conditions, such as tumor metastasis, kidney disorders, and in the treatment of inflammatory conditions. However, pharmacological studies on this receptor have been impeded by the limited reported availability of stable, potent and selective P2Y2 R antagonists. This article describes the design and synthesis of AR-C118925, a potent and selective non-nucleotide antagonist of the P2Y2 receptor discovered using the endogenous P2Y2 R agonist UTP as the chemical starting point...

A homology model of the nucleotide-activated P2Y2 R was created based on the X-ray structures of the P2Y1 receptor. Docking studies were performed, and receptor mutants were created to probe the identified binding interactions. Mutation of residues predicted to interact with the ribose (Arg110) and the phosphates of the nucleotide agonists (Arg265, Arg292) or that contribute indirectly to binding (Tyr288) abolished activity. The Y114F, R194A, and F261A mutations led to inactivity of diadenosine tetraphosphate and to a reduced response of UTP...