Pharmacology of P2Y receptors

Kügelgen, Ivar von

doi:10.1016/j.brainresbull.2019.03.010

Cited by 69 publications

(73 citation statements)

References 327 publications

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“…The metabotropic P2Y 1 receptor (P2Y 1 R), formerly known as the P 2T receptor, has been identified and cloned (Webb et al, 1993;Baranska et al, 2017) and has features typical of G protein-coupled receptors, i.e., an extracellular N-terminus and an intracellular C-terminus, seven hydrophobic transmembrane regions, three extracellular loops and three intracellular loops (von Kugelgen and Hoffmann, 2016). The P2Y 1 R has a distinctive rank order of agonist potencies (i.e., 2-methylthio-ADP > ADP > ATP) and its activation induces canonical Gα q signaling leading to phospholipase C activation and generation of the second messengers inositol 1, 4, 5-trisphosphate (IP 3 ) and diacylglycerol that increase [Ca 2+ ] i and protein kinase C (PKC) activity, respectively (von Kugelgen and Wetter, 2000;Abbracchio et al, 2006;Baranska et al, 2017;von Kugelgen, 2019). Additionally, P2Y 1 R activation stimulates metalloprotease-dependent transactivation of the epidermal growth factor receptor (EGFR) (Buvinic et al, 2007) and mitogen-activated protein kinase (MAPK) activity through activation of phosphatidylinositol 3-kinase, Src kinase and PKC (Sellers et al, 2001;Baranska et al, 2017).…”

Section: The Role Of P2 Receptors In Salivary Gland Functionmentioning

confidence: 99%

P2 Receptors as Therapeutic Targets in the Salivary Gland: From Physiology to Dysfunction

et al. 2020

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Although often overlooked in our daily lives, saliva performs a host of necessary physiological functions, including lubricating and protecting the oral cavity, facilitating taste sensation and digestion and maintaining tooth enamel. Therefore, salivary gland dysfunction and hyposalivation, often resulting from pathogenesis of the autoimmune disease Sjögren's syndrome or from radiotherapy of the head and neck region during cancer treatment, severely reduce the quality of life of afflicted patients and can lead to dental caries, periodontitis, digestive disorders, loss of taste and difficulty speaking. Since their initial discovery in the 1970s, P2 purinergic receptors for extracellular nucleotides, including ATP-gated ion channel P2X and G protein-coupled P2Y receptors, have been shown to mediate physiological processes in numerous tissues, including the salivary glands where P2 receptors represent a link between canonical and non-canonical saliva secretion. Additionally, extracellular nucleotides released during periods of cellular stress and inflammation act as a tissue alarmin to coordinate immunological and tissue repair responses through P2 receptor activation. Accordingly, P2 receptors have gained widespread clinical interest with agonists and antagonists either currently undergoing clinical trials or already approved for human use. Here, we review the contributions of P2 receptors to salivary gland function and describe their role in salivary gland dysfunction. We further consider their potential as therapeutic targets to promote physiological saliva flow, prevent salivary gland inflammation and enhance tissue regeneration.

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Section: The Role Of P2 Receptors In Salivary Gland Functionmentioning

confidence: 99%

P2 Receptors as Therapeutic Targets in the Salivary Gland: From Physiology to Dysfunction

et al. 2020

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“…Nucleotides are an important class of signaling molecules in the nervous system, what was discovered already fifty years ago (Burnstock, 1972;Burnstock, 2007). ATP and other extracellular nucleotides released by neurons (Lopatář et al, 2015) as well as glia (Illes et al, 2019) are responsible for the communication between different CNS cells (Abbracchio et al, 2009): metabotropic, G-coupled P2Y receptors (Abbracchio et al, 2006;von Kügelgen, 2019) and P2X receptors which serve as plasma membrane ion channels (Kawate, 2017). All nucleotide receptors are characterized by different ligand affinity and downstream signaling properties.…”

Section: Introductionmentioning

confidence: 99%

P2X7 receptor activity landscape in rat and human glioma cell lines

2020

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P2X7 is a commonly expressed purinergic receptor, which functions as a cation-permeable channel in the plasma membrane. In certain circumstances, the receptor may also form a large transmembrane pore what results in cell death. P2X7 receptors control numerous physiological and pathological cellular processes and their overexpression is often associated with cancer progression. As nucleotides are important signaling molecules in the central nervous system, P2X7 plays also an important but ambiguous role in glioma biology with contrary observations originating from different glioma models. Therefore, the aim of our research was to investigate P2X7 receptor expression and functions in three human (U-87 MG, U-138 MG, U-251 MG) and one rat (C6) glioma cell lines. Although the receptor mRNA and protein were present in all the studied cells, we found profound differences in their level. We also encountered a problem with one human cell lines authenticity (U-87 MG) and excluded it from most of the experiments. Interestingly, there was no clear dependency between P2X7 receptor level, calcium signal and pore formation ability in the studied glioma lines. In U-138 human cell line, the receptor seemed to be inactive, while in U-251 human and C6 rat cell line its activation resulted in calcium influx and large pore formation. However, the viability of studied cells upon the administration of specific P2X7 agonist -BzATP -was not affected for U-138 and U-251, whereas for C6 cells a stimulatory effect was observed. Our results stress the variability of P2X7 signaling in glioma models and the need for future research which would take into account the complicated landscape of the receptor signaling in the brain.

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“…Drug concentrations were selected according to reported selectivity and EC 50 s in human cells (Abbracchio et al, 2006; Brunschweiger and Müller, 2006; Kügelgen and Bonn, 2008). …”

Section: Methodsmentioning

confidence: 99%

UTP – Gated Signaling Pathways of 5-HT Release from BON Cells as a Model of Human Enterochromaffin Cells

et al. 2017

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Background: Enterochromaffin cells (EC) synthesize and release 5-HT and ATP to trigger or modulate gut neural reflexes and transmit information about visceral/pain sensation. Alterations in 5-HT signaling mechanisms may contribute to the pathogenesis of IBD or IBS, but the pharmacologic or molecular mechanisms modulating Ca2+-dependent 5-HT release are not understood. Previous studies indicated that purinergic signaling via ATP and ADP is an important mechanism in modulation of 5-HT release. However, EC cells also respond to UTP and UDP suggesting uridine triphosphate receptor and signaling pathways are involved as well. We tested the hypothesis that UTP is a regulator of 5-HT release in human EC cells.Methods: UTP signaling mechanisms were studied in BON cells, a human EC model, using Fluo-4/Ca2+imaging, patch-clamp, pharmacological analysis, immunohistochemistry, western blots and qPCR. 5-HT release was monitored in BON or EC isolated from human gut surgical specimens (hEC).Results: UTP, UTPγS, UDP or ATP induced Ca2+oscillations in BON. UTP evoked a biphasic concentration-dependent Ca2+response. Cells responded in the order of UTP, ATP > UTPγS > UDP >> MRS2768, BzATP, α,β-MeATP > MRS2365, MRS2690, and NF546. Different proportions of cells activated by UTP and ATP also responded to UTPγS (P2Y4, 50% cells), UDP (P2Y6, 30%), UTPγS and UDP (14%) or MRS2768 (<3%). UTP Ca2+responses were blocked with inhibitors of PLC, IP3R, SERCA Ca2+pump, La3+sensitive Ca2+channels or chelation of intracellular free Ca2+ by BAPTA/AM. Inhibitors of L-type, TRPC, ryanodine-Ca2+pools, PI3-Kinase, PKC or SRC-Kinase had no effect. UTP stimulated voltage-sensitive Ca2+currents (ICa), Vm-depolarization and inhibited IK (not IA) currents. An IKv7.2/7.3 K+ channel blocker XE-991 mimicked UTP-induced Vm-depolarization and blocked UTP-responses. XE-991 blocked IK and UTP caused further reduction. La3+ or PLC inhibitors blocked UTP depolarization; PKC inhibitors, thapsigargin or zero Ca2+buffer did not. UTP stimulated 5-HT release in hEC expressing TPH1, 5-HT, P2Y4/P2Y6R. Zero-Ca2+buffer augmented Ca2+responses and 5-HT release.Conclusion: UTP activates a predominant P2Y4R pathway to trigger Ca2+oscillations via internal Ca2+mobilization through a PLC/IP3/IP3R/SERCA Ca2+signaling pathway to stimulate 5-HT release; Ca2+influx is inhibitory. UTP-induced Vm-depolarization depends on PLC signaling and an unidentified K channel (which appears independent of Ca2+oscillations or Ica/VOCC). UTP-gated signaling pathways triggered by activation of P2Y4R stimulate 5-HT release.

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Pharmacology of P2Y receptors

Cited by 69 publications

References 327 publications

P2 Receptors as Therapeutic Targets in the Salivary Gland: From Physiology to Dysfunction

P2 Receptors as Therapeutic Targets in the Salivary Gland: From Physiology to Dysfunction

P2X7 receptor activity landscape in rat and human glioma cell lines

UTP – Gated Signaling Pathways of 5-HT Release from BON Cells as a Model of Human Enterochromaffin Cells

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