Functional and molecular evidence for heteromeric association of P2Y1 receptor with P2Y2 and P2Y4 receptors in mouse granulocytes

Ribeiro-Filho, Antonio C.; Buri, Marcus V.; Barros, Carlos Castilho; Dreyfuss, Juliana Luporini; Nader, Helena B.; Justo, Giselle Z.; Craveiro, Rogerio B.; Pesquero, João Bosco; Miranda, Antônio; Ferreira, Alice Teixeira; Paredes‐Gamero, Edgar Julian

doi:10.1186/s40360-016-0072-y

Cited by 10 publications

(3 citation statements)

References 30 publications

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“…We aimed to assess the expression of P 2 Y 12 receptors in monocytes and macrophages. RT-PCR has been frequently used to determine the expression levels of purinergic receptors in blood leukocytes 41 , 42 . Using the five common methods of assessing monocytes with flow cytometry or microscopy (elutriation, cell sorting, blood smear, Ficoll density gradient, whole-blood flow cytometry), we demonstrated that a significant proportion of monocytes carry platelets on their surface, even if isolated with the least activating purification methods, elutriation and cell sorting.…”

Section: Discussionmentioning

confidence: 99%

P2Y12 receptor blockers are anti-inflammatory drugs inhibiting both circulating monocytes and macrophages including THP-1 cells

Siegel

Sander

Fricke

et al. 2021

Sci Rep

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P2Y12 blockade improves patient outcomes after myocardial infarction. As well as antithrombotic effects, anti-inflammatory effects may contribute to this beneficial clinical outcome. Here we aimed to identify potential anti-inflammatory effects of P2Y12 receptor blockers on monocytes and macrophages. Using flow cytometry, migration assays, flow chambers and RNA microarrays, we investigated the effects of adenosine diphosphate (ADP) and P2Y12 receptor blockers on blood monocytes, THP-1 monocytes and THP-1 monocytes after differentiation to macrophages. P2Y12 -expressing platelets can form aggregates with monocytes in circulating blood. Mediated by platelets, ADP results in activation of the integrin receptor Mac-1 on blood monocytes, as detected by the conformation-specific single-chain antibody MAN-1. Via the same association with platelets, THP-1 monocyte adhesion to the endothelial intercellular adhesion molecule 1 (ICAM-1) is induced by ADP. P2Y12 receptor blockers prevent these ADP effects on monocytes. Interestingly, in contrast to THP-1 monocytes, THP-1 monocytes, after differentiation to macrophages, directly expressed the P2Y12 receptor and consequently ADP was found to be a potent chemoattractant. Again, P2Y12 receptor blockers antagonised this effect. Accordingly, stimulation of THP-1 macrophages with ADP caused a substantial change in gene expression pattern and upregulation of several genes associated with inflammation and atherogenesis. These data establish novel anti-inflammatory effects of P2Y12 receptor blockers on monocytes and macrophages, which are expected to contribute to cardiovascular risk reduction.

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Section: Discussionmentioning

confidence: 99%

P2Y12 receptor blockers are anti-inflammatory drugs inhibiting both circulating monocytes and macrophages including THP-1 cells

Siegel

Sander

Fricke

et al. 2021

Sci Rep

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“…Physical interaction between different recombinant subtypes also occurs, for example P2Y 4 R and P2Y 6 R [ 85 ], P2Y 1 R and P2Y 11 R [ 86 , 87 ], P2Y 1 R with P2Y 2 R, P2Y 12 R and P2Y 13 R, P2Y 2 R with P2Y 12 R and P2Y 13 R, and P2Y 12 R with P2Y 13 R [ 83 ] and P2Y 1 R with P2Y 2 R or P2Y 4 R [ 88 ]. Changes in the properties of P2YR following formation of heterodimers have also been reported.…”

Section: This Is Now—p2 Receptors In the 2020smentioning

confidence: 99%

That was then, this is now: the development of our knowledge and understanding of P2 receptor subtypes

Kennedy

2021

Purinergic Signalling

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P2 receptors are present in virtually all tissues and cell types in the human body, and they mediate the physiological and pharmacological actions of extracellular purine and pyrimidine nucleotides. They were first characterised and named by Geoff Burnstock in 1978, then subdivided into P2X and P2Y purinoceptors in 1985 on the basis of pharmacological criteria in functional studies on native receptors. Molecular cloning of receptors in the 1990s revealed P2X receptors to comprise seven different subunits that interact to produce functional homo- and heterotrimeric ligand-gated cation channels. A family of eight P2Y G protein–coupled receptors were also cloned, which can form homo- and heterodimers. Deep insight into the molecular mechanisms of agonist and antagonist action has been provided by more recent determination of the tertiary and quaternary structures of several P2X and P2Y receptor subtypes. Agonists and antagonists that are highly selective for individual subtypes are now available and some are in clinical use. This has all come about because of the intelligence, insight and drive of the force of nature that was Geoff Burnstock.

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“…P2X1 receptor is involved in endotoxemia by its participation in the chemotaxis of neutrophils [75], P2X1 −/− mouse shows reduced inflammatory response with resistance to LPSinduced death [76]. Additionally, the evaluation of P2 receptor expression in murine granulocytes showed the presence of the P2Y1, P2Y2, and P2Y4 receptors, with heteromeric association of the P2Y1/P2Y2 and P2Y1/P2Y4 receptors [77].…”

Section: Presence and Participation Of P2 Receptors In The Immune Systemmentioning

confidence: 99%

Involvement of P2 receptors in hematopoiesis and hematopoietic disorders, and as pharmacological targets

Filippin

Souza

Júnior

et al. 2019

Purinergic Signalling

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Several reports have shown the presence of P2 receptors in hematopoietic stem cells (HSCs). These receptors are activated by extracellular nucleotides released from different sources. In the hematopoietic niche, the release of purines and pyrimidines in the milieu by lytic and nonlytic mechanisms has been described. The expression of P2 receptors from HSCs until maturity is still intriguing scientists. Several reports have shown the participation of P2 receptors in events associated with modulation of the immune system, but their participation in other physiological processes is under investigation. The presence of P2 receptors in HSCs and their ability to modulate this population have awakened interest in exploring the involvement of P2 receptors in hematopoiesis and their participation in hematopoietic disorders. Among the P2 receptors, the receptor P2X7 is of particular interest, because of its different roles in hematopoietic cells (e.g., infection, inflammation, cell death and survival, leukemias and lymphomas), making the P2X7 receptor a promising pharmacological target. Additionally, the role of P2Y12 receptor in platelet activation has been well-documented and is the main example of the importance of the pharmacological modulation of P2 receptor activity. In this review, we focus on the role of P2 receptors in the hematopoietic system, addressing these receptors as potential pharmacological targets.

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Functional and molecular evidence for heteromeric association of P2Y1 receptor with P2Y2 and P2Y4 receptors in mouse granulocytes

Cited by 10 publications

References 30 publications

P2Y12 receptor blockers are anti-inflammatory drugs inhibiting both circulating monocytes and macrophages including THP-1 cells

P2Y12 receptor blockers are anti-inflammatory drugs inhibiting both circulating monocytes and macrophages including THP-1 cells

That was then, this is now: the development of our knowledge and understanding of P2 receptor subtypes

Involvement of P2 receptors in hematopoiesis and hematopoietic disorders, and as pharmacological targets

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