Purinergic Signalling in the Reproductive System

Gorodeski, George I.

doi:10.1016/j.autneu.2015.04.008

Cited by 29 publications

(18 citation statements)

References 313 publications

(413 reference statements)

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“…Similarly, activation of P2X4 at alkaline pH would also provide a feedback mechanism that would ensure activation of CCs by ATP following an increase in luminal pH. Several diseases, including male infertility, are associated with a defect in purinergic regulation (Mulryan et al 2000;Banks et al 2010;Burnstock, 2014;Kauffenstein et al 2014;Gorodeski, 2015;Menzies et al 2017). Activation of P2X4 and increased adenosine production by luminal alkalinization may thus provide a fine-tuning mechanism for the maintenance of the acidic luminal environment.…”

Section: Discussionmentioning

confidence: 99%

Unravelling purinergic regulation in the epididymis: activation of V‐ATPase‐dependent acidification by luminal ATP and adenosine

Battistone

Merkulova

Park

et al. 2019

The Journal of Physiology

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Key points In the epididymis, elaborate communication networks between epithelial cells are important with respect to establishing an optimal acidic luminal environment for the maturation and storage of spermatozoa, which is essential for male fertility. Proton secretion by epididymal clear cells is achieved via the proton pumping V‐ATPase located in their apical membrane. In the present study, we dissect the molecular mechanisms by which clear cells respond to luminal ATP and adenosine to modulate their acidifying activity via the adenosine receptor ADORA2B and the pH‐sensitive ATP receptor P2X4. We demonstrate that the hydrolysis of ATP to produce adenosine by ectonucleotidases plays a key role in V‐ATPase‐dependent proton secretion, and is part of a feedback loop that ensures acidification of the luminal compartment These results help us better understand how professional proton‐secreting cells respond to extracellular cues to modulate their functions, and how they communicate with neighbouring cells. Abstract Cell–cell cross‐talk is crucial for the dynamic function of epithelia, although how epithelial cells detect and respond to variations in extracellular stimuli to modulate their environment remains incompletely understood. In the present study, we used the epididymis as a model system to investigate epithelial cell regulation by luminal factors. In the epididymis, elaborate communication networks between the different epithelial cell types are important for establishing an optimal acidic luminal environment for the maturation and storage of spermatozoa. In particular, clear cells (CCs) secrete protons into the lumen via the proton pumping V‐ATPase located in their apical membrane, a process that is activated by luminal alkalinization. However, how CCs detect luminal pH variations to modulate their function remains uncharacterized. Purinergic regulation of epithelial transport is modulated by extracellular pH in other tissues. In the present study, functional analysis of the mouse cauda epididymis perfused in vivo showed that luminal ATP and adenosine modulate the acidifying activity of CCs via the purinergic ADORA2B and P2X4 receptors, and that luminal adenosine content is itself regulated by luminal pH. Altogether, our observations illustrate mechanisms by which CCs are activated by pH sensitive P2X4 receptor and ectonucleotidases, providing a feedback mechanism for the maintenance of luminal pH. These novel mechanisms by which professional proton‐secreting cells respond to extracellular cues to modulate their functions, as well as how they communicate with neighbouring cells, might be translatable to other acidifying epithelia.

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Section: Discussionmentioning

confidence: 99%

Unravelling purinergic regulation in the epididymis: activation of V‐ATPase‐dependent acidification by luminal ATP and adenosine

Battistone

Merkulova

Park

et al. 2019

The Journal of Physiology

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“…Reviews are available about purinergic signalling in the reproductive system in both health and disease ( Burnstock, 2014c ; Gorodeski, 2015 ).…”

Section: Diseases Of the Reproductive Systemmentioning

confidence: 99%

Purinergic Signalling: Therapeutic Developments

2017

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Purinergic signalling, i.e., the role of nucleotides as extracellular signalling molecules, was proposed in 1972. However, this concept was not well accepted until the early 1990’s when receptor subtypes for purines and pyrimidines were cloned and characterised, which includes four subtypes of the P1 (adenosine) receptor, seven subtypes of P2X ion channel receptors and 8 subtypes of the P2Y G protein-coupled receptor. Early studies were largely concerned with the physiology, pharmacology and biochemistry of purinergic signalling. More recently, the focus has been on the pathophysiology and therapeutic potential. There was early recognition of the use of P1 receptor agonists for the treatment of supraventricular tachycardia and A2A receptor antagonists are promising for the treatment of Parkinson’s disease. Clopidogrel, a P2Y12 antagonist, is widely used for the treatment of thrombosis and stroke, blocking P2Y12 receptor-mediated platelet aggregation. Diquafosol, a long acting P2Y2 receptor agonist, is being used for the treatment of dry eye. P2X3 receptor antagonists have been developed that are orally bioavailable and stable in vivo and are currently in clinical trials for the treatment of chronic cough, bladder incontinence, visceral pain and hypertension. Antagonists to P2X7 receptors are being investigated for the treatment of inflammatory disorders, including neurodegenerative diseases. Other investigations are in progress for the use of purinergic agents for the treatment of osteoporosis, myocardial infarction, irritable bowel syndrome, epilepsy, atherosclerosis, depression, autism, diabetes, and cancer.

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“…All P2X-receptors get exclusively activated by ATP, which induces Ca 2+ influx, causing changes in cell homeostasis [6]. P2RX4 is expressed on cells of the reproductive system [7], in the airways [8-10], on microglia [11] and on cardiac myocytes [12] as well as neutrophils, eosinophils, mast cells, T- and B-lymphocytes [13, 14]. Besides its role in the nervous system, P2RX4 signaling also exerts immunomodulatory functions such as inducing inflammatory-mediated prostaglandin E2 (PGE2) release and facilitating T cell activation at the immune synapse [15, 16].…”

Section: Introductionmentioning

confidence: 99%

P2rx4 deficiency in mice alleviates allergen-induced airway inflammation

et al. 2016

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Compelling evidences point out a crucial role for extracellular nucleotides such as adenosine triphosphate (ATP) during inflammatory conditions. Once released into the extracellular space, ATP modulates migration, maturation and function of various inflammatory cells via activating of purinergic receptors of the P2Y- and P2X- family. P2RX4 is an ATP-guided ion channel expressed on structural cells such as alveolar epithelial and smooth muscle cells as well as inflammatory cells including macrophages, dendritic cells (DCs) and T cells. P2RX4 has been shown to interact with P2RX7 and promote NLRP3 inflammasome activation. Although P2RX7 has already been implicated in allergic asthma, the role of P2RX4 in airway inflammation has not been elucidated yet. Therefore, we used a selective pharmacological antagonist and genetic ablation to investigate the role of P2RX4 in an ovalbumin (OVA) driven model of allergen-induced airway inflammation (AAI). Both, P2RX4 antagonist 5-BDBD treatment and P2rx4 deficiency resulted in an alleviated broncho alveolar lavage fluid eosinophilia, peribronchial inflammation, Th2 cytokine production and bronchial hyperresponsiveness. Furthermore, P2rx4-deficient bone marrow derived DCs (BMDCs) showed a reduced IL-1ß production in response to ATP accompanied by a decreased P2rx7 expression and attenuated Th2 priming capacity compared to wild type (WT) BMDCs in vitro. Moreover, mice adoptively transferred with P2rx4-deficient BMDCs exhibit a diminished AAI in vivo. In conclusion our data suggests that P2RX4-signaling contributes to AAI pathogenesis by regulating DC mediated Th2 cell priming via modulating IL-1ß secretion and selective P2RX4-antagonists might be a new therapeutic option for allergic asthma.

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Purinergic Signalling in the Reproductive System

Cited by 29 publications

References 313 publications

Unravelling purinergic regulation in the epididymis: activation of V‐ATPase‐dependent acidification by luminal ATP and adenosine

Unravelling purinergic regulation in the epididymis: activation of V‐ATPase‐dependent acidification by luminal ATP and adenosine

Purinergic Signalling: Therapeutic Developments

P2rx4 deficiency in mice alleviates allergen-induced airway inflammation

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