更新于：2024-11-01

P2Y1 x P2Y13 receptor

更新于：2024-11-01

基本信息

关联

项与 P2Y1 x P2Y13 receptor 相关的药物

MRS 2603

靶点

P2Y1 x P2Y13 receptor

作用机制

P2Y1拮抗剂 [+1]

在研机构

Gwangju Institute of Science & Technology

原研机构

Gwangju Institute of Science & Technology

在研适应症-

非在研适应症-

最高研发阶段临床前

首次获批国家/地区-

首次获批日期1800-01-20

100 项与 P2Y1 x P2Y13 receptor 相关的临床结果

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100 项与 P2Y1 x P2Y13 receptor 相关的转化医学

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0 项与 P2Y1 x P2Y13 receptor 相关的专利（医药）

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项与 P2Y1 x P2Y13 receptor 相关的文献（医药）

2024-01-01·Journal of Histochemistry & Cytochemistry

ADP-mediated Modulation of Intracellular Calcium Responses in Chromaffin Cells: The Role of Ectonucleoside Triphosphate Diphosphohydrolase 2 on Rat Adrenal Medulla Function

Article

作者: Sato, Kenichi ; Maesawa, Satsuki ; Sakanoue, Wakana ; Yamamoto, Yoshio ; Yokoyama, Takuya ; Hirakawa, Masato ; Saino, Tomoyuki ; Shiraishi, Hirohisa

The present study investigated the localization and the adenosine 5′-triphosphate (ATP)-degrading function of the plasma membrane-bound ecto-nucleotidase, ectonucleoside triphosphate diphosphohydrolase 2 (NTPDase2), in the rat adrenal medulla. The effect of ATP degradation product, adenosine 5′-diphosphate (ADP), on carbachol (CCh)-induced intracellular Ca2+ ([Ca2+]i) responses in adrenal chromaffin cells was examined using calcium imaging. NTPDase2-immunoreactive cells were distributed between chromaffin cells. NTPDase2-immunoreactive cells were immunoreactive for glial fibrillary acidic protein and S100B, suggesting that they were sustentacular cells. NTPDase2-immunoreactive cells surrounded chromaffin cells immunoreactive for vesicular nucleotide transporter and P2Y12 ADP-selective purinoceptors. In ATP bioluminescence assays using adrenal medullary slices, ATP was rapidly degraded and its degradation was attenuated by the NTPDase inhibitors sodium polyoxotungstate (POM-1) and 6- N, N-diethyl-d-β,γ-dibromomethylene ATP (ARL67156). ADP inhibited CCh-induced [Ca2+]i increases of chromaffin cells in adrenal medullary slices. The inhibition of CCh-induced [Ca2+]i increases by ADP was blocked by the P2Y12 purinoceptor antagonist AZD1283. CCh-induced [Ca2+]i increases were also inhibited by the P2Y1, P2Y12, and P2Y13 purinoceptor agonist 2-methylthioadenosine diphosphate trisodium (2MeSADP), in combination with the P2Y1 purinoceptor antagonist MRS2179. These results suggest that sustentacular cells express NTPDase2 to degrade ATP released from adrenal chromaffin cells, and ADP modulates the excitability of chromaffin cells via P2Y12 purinoceptors to regulate catecholamine release during preganglionic sympathetic stimuli. (J Histochem Cytochem 72: 41–60, 2024)

2023-12-01·The EMBO Journal

Systematic P2Y receptor survey identifies P2Y11 as modulator of immune responses and virus replication in macrophages

Article

作者: Oubraham, Lila ; Paludan, Søren Riis ; Stafford, Che ; Engleitner, Thomas ; Ebert, Thomas ; Rad, Roland ; Andersen, Line Lykke ; Nagl, Dennis ; O'Duill, Fionan ; Pichlmair, Andreas ; Urban, Christian ; Winheim, Elena ; Krug, Anne ; Huang, Yiqi ; Hornung, Veit

AbstractThe immune system is in place to assist in ensuring tissue homeostasis, which can be easily perturbed by invading pathogens or nonpathogenic stressors causing tissue damage. Extracellular nucleotides are well known to contribute to innate immune signaling specificity and strength, but how their signaling is relayed downstream of cell surface receptors and how this translates into antiviral immunity is only partially understood. Here, we systematically investigated the responses of human macrophages to extracellular nucleotides, focusing on the nucleotide‐sensing GPRC receptors of the P2Y family. Time‐resolved transcriptomic analysis showed that adenine‐ and uridine‐based nucleotides induce a specific, immediate, and transient cytokine response through the MAPK signaling pathway that regulates transcriptional activation by AP‐1. Using receptor trans‐complementation, we identified a subset of P2Ys (P2Y1, P2Y2, P2Y6, and P2Y11) that govern inflammatory responses via cytokine induction, while others (P2Y4, P2Y11, P2Y12, P2Y13, and P2Y14) directly induce antiviral responses. Notably, P2Y11 combined both activities, and depletion or inhibition of this receptor in macrophages impaired both inflammatory and antiviral responses. Collectively, these results highlight the underappreciated functions of P2Y receptors in innate immune processes.

2022-02-01·American Journal of Respiratory and Critical Care Medicine1区 · 医学

Targeting the P2Y₁₃ Receptor Suppresses IL-33 and HMGB1 Release and Ameliorates Experimental Asthma

1区 · 医学

Article

作者: Bowler, Simon ; Bissell, Alec ; Lu, Wenying ; Collinson, Natasha ; Spann, Kirsten ; Hasnain, Sumaira Z. ; Martinez, Laurent O. ; Sikder, Md Al Amin ; Ferreira, Manuel A. R. ; Yarlagadda, Tejasri ; Curren, Bodie F. ; Sohal, Sukhwinder S. ; Handoko, Herlina Y. ; Phipps, Simon ; Lynch, Jason P. ; Rashid, Ridwan B. ; Robaye, Bernard ; Hartel, Gunter ; Burr, Lucy D. ; Simpson, Jennifer ; Rahman, Muhammed Mahfuzur ; Sebina, Ismail ; Ullah, Md Ashik ; Ngo, Sylvia ; Werder, Rhiannon B. ; Rittchen, Sonja ; Martin, Megan

Rationale: The alarmins IL-33 and HMGB1 (high mobility group box 1) contribute to type 2 inflammation and asthma pathogenesis. Objectives: To determine whether P2Y₁₃-R (P2Y₁₃ receptor), a purinergic GPCR (G protein-coupled receptor) and risk allele for asthma, regulates the release of IL-33 and HMGB1. Methods: Bronchial biopsy specimens were obtained from healthy subjects and subjects with asthma. Primary human airway epithelial cells (AECs), primary mouse AECs, or C57Bl/6 mice were inoculated with various aeroallergens or respiratory viruses, and the nuclear-to-cytoplasmic translocation and release of alarmins was measured by using immunohistochemistry and an ELISA. The role of P2Y₁₃-R in AEC function and in the onset, progression, and exacerbation of experimental asthma was assessed by using pharmacological antagonists and mice with P2Y₁₃-R gene deletion. Measurements and Main Results: Aeroallergen exposure induced the extracellular release of ADP and ATP, nucleotides that activate P2Y₁₃-R. ATP, ADP, and aeroallergen (house dust mite, cockroach, or Alternaria antigen) or virus exposure induced the nuclear-to-cytoplasmic translocation and subsequent release of IL-33 and HMGB1, and this response was ablated by genetic deletion or pharmacological antagonism of P2Y13. In mice, prophylactic or therapeutic P2Y₁₃-R blockade attenuated asthma onset and, critically, ablated the severity of a rhinovirus-associated exacerbation in a high-fidelity experimental model of chronic asthma. Moreover, P2Y₁₃-R antagonism derepressed antiviral immunity, increasing IFN-λ production and decreasing viral copies in the lung. Conclusions: We identify P2Y₁₃-R as a novel gatekeeper of the nuclear alarmins IL-33 and HMGB1 and demonstrate that the targeting of this GPCR via genetic deletion or treatment with a small-molecule antagonist protects against the onset and exacerbations of experimental asthma.