Its stimulation with the selective agonist UDP incremented cell viability and progesterone but did not affect estradiol production. These results suggested that purines acting through P2Y6 regulate luteal body viability and steroidogenic function. These observations were confirmed by a later study that demonstrated the participation of apoptotic marker caspase-3 [ 40 ].
This effect was apparently not consistent with previous observations regarding ATP actions in GLC, but it could be explained by the differential sensitivity of distinct P2 receptors [ 41 ]. It is possible that extracellular concentration of ATP and the expression of P2 receptor determine the specific effect of purinergic stimulation. Recently it was described that the P2X7 receptor is expressed in mouse luteal cells.
Its activation with ATP or BzATP induced an antiproliferative effect by regulating the expression of cyclin D2 and cyclin E2, as well as the phosphorylation of mitogen-activated protein kinase p38 [ 42 ]. The result suggests a role for the P2X7 receptor in luteal body function. The purinergic system is well represented in GLC. A set of purinergic receptors can modulate basic cellular processes such as proliferation, apoptosis, and steroidogenesis. Growing evidence indicates that purines are important regulators of GLC, but further studies are necessary to reinforce their role in ovarian physiology.
The theca cell layer is an enclosure of cells that surrounds the oocyte during folliculogenesis. It is crucial for maintaining the structural integrity of the follicle as well as for regulating nutrient influx to the avascular GCL [ 43 , 44 ]. Theca is also the site for the synthesis of steroid hormones, specifically androgens testosterone and dihydrotestosterone , from acetate or cholesterol into estrogens by granulosa cells in an LH-dependent manner [ 3 ]. In addition, theca is the only component of the follicle that is innervated by sympathetic and parasympathetic nervous systems, implicating that this layer functions as a complex integrator of endocrine and neural information [ 45 ].
When a primary follicle has one or two layers of granulosa cells, an outer granulosa cell layer differentiates into theca cells and, together with recruited theca precursor cells from the stroma, forms the theca cell layer surrounding the oocyte [ 44 , 46 ]. Some pathophysiological reproduction-related conditions such as infertility or polycystic ovarian syndrome are often the result of dysfunctional activity of theca cells during ovulation and follicle development [ 47 , 48 ]. The theca cell layer contacts the rich microvasculature system surrounding each follicle and integrates signals from autonomic innervation [ 49 ].
It has been demonstrated that ATP can be co-released with noradrenaline from terminals of the peripheral nervous system [ 50 ] and as a result of mechanical stress and changes in cell volume in the oocyte [ 51 ]; thus, ATP is a relevant modulator of cellular communication between the theca cell layer and surrounding oocyte cells. Purinergic signaling has been described in female reproductive organs, and evidence has shown that ATP in the extracellular space participates in the physiological regulation of the ovary [ 52 ].
The first characterization of purinergic signaling in theca cells showed the functional expression, and activation of P2X7 receptors induced cell death, an important mechanism for the onset and physiological progression of follicle atresia [ 53 ]. P2X7 receptors have also been associated with the inhibition of luteal cell survival and proliferation, pointedly in small luteal cells, which have been suggested as theca-derived luteal cells [ 42 ].
In this system, stimulation of the expressed P2Y receptors with UTP in cultured theca cells induces the activation of mitogenic-signaling pathways that promote cell proliferation [ 54 ]. This finding is a relevant pathophysiological indication, since a slow but maintained proliferation takes place in polycystic ovarian syndrome [ 47 ]. Furthermore, an interaction between adenosine receptor A2 and P2Y receptors has been described in theca of Xenopus ovarian follicles.
The authors suggested that this association took place when both the epithelial and theca cell layers of the oocyte were intact [ 55 ]. Collectively, these findings suggest that a tight regulation of purinergic expression and signaling must be in place for the theca cell layer to function properly and communicate with neighboring cells.
The organized structure of the cumulus-enclosed oocyte CEO complex corresponds to a specialized GLC surrounding the oocyte. Cumulus cells secrete factors to regulate oocyte maturation and maintain meiotic arrest [ 56 ]. It was reported that porcine and murine follicular fluid contains purine compounds that presumably participate in CEO functions, suggesting that it could be an important signal to trigger physiological events [ 57 , 56 ].
Until recently, purinergic receptors were identified and characterized in CEO, indicating that purinergic signaling participates in CEO physiology [ 58 , 59 ]. When Eppig et al. In these studies, the concentration of nucleotide compounds in murine follicular fluid was determined using high-performance liquid chromatography HPLC.
They identified two purine compounds: hypoxanthine and ADO, with concentrations in ranges of 2—4 and 0. They also showed that these purines affected the CEO by maintaining the meiotic arrest [ 56 ]. Eppig et al. This observation contrasted with that of other laboratories which had failed to detect inhibitory activity in follicular fluid.
In , two reports elucidated which purinergic receptor was expressed in CEO cells. In another report, the responses generated by a putative purinergic receptor expressed in the CEO were identified and characterized. Employing the voltage clamp technique with two electrodes, the authors observed depolarization responses when extracellular ATP was applied. RT-PCR analysis revealed a product correspondent to the P2Y2 receptor, suggesting that calcium mobilization is dependent on this receptor.
The authors concluded that both purinergic receptors and ionic channels were located in CEO cells that transmitted their electrical signals to the oocyte via gap junctions [ 58 ]. These data support the idea that P2Y2 is an important element in paracrine signaling in regulating CEO complex physiology. Future studies are required to determine the mechanisms involved in CEO functions and oocyte maturation by ATP stimulation. Ovarian surface epithelium OSE is a monolayer surrounding the ovary. It is composed of a single flat layer of squamous-to-cuboidal epithelial cells featuring distinguished epithelial and mesenchymal markers.
OSE is essential during ovulation to promote follicular rupture and release the oocyte [ 62 ] and for postovulatory repair of the ovary [ 63 ]. Initial and important studies were led by Nelly Auersperg to characterize and identify epithelial and mesenchymal markers, hormonal and growth factor receptors, and physiopathological role, with the idea that OSE is determinant in the onset of ovarian carcinoma [ 64 ].
During ovulation, the OSE is involved in three main phases: apex formation, rupture, and repair [ 65 ]. The initial phase starts with the actions of luteinizing hormone LH and triggers apex formation at the rupture site of the ovarian surface [ 66 ]. In the second phase, OSE cells initiate a lytic cascade [ 62 , 67 , 68 ], releasing proteolytic enzymes to degrade the basal lamina, the tunica albuginea, and ovarian cells of the mature follicle.
The digested matrix, follicular wall disintegration, and peeling of OSE cells create a wound stigma that facilitates oocyte release. Finally, the repair phase consists in wound closure by postovulatory cell proliferation and migration [ 69 ]. Nevertheless, the signaling involved in these phases during ovulation in the OSE is unclear. Purinergic signaling was suggested as a part of intraovarian modulation due to a certain purinergic receptor expressed in the OSE committed in physiological processes. Recently, Vazquez-Cuevas et al. These findings contribute to the idea that local factors, such as ATP, may participate in a proposed cyclic proliferation-death equilibrium of the OSE cell layer in the ovulatory process.
Understanding purinergic signaling and receptor expression in the OSE will help to decipher the mechanisms underlying ovary physiology and pathology. However, more studies need to contribute evidence related to homeostasis and postovulatory repair. Some studies regarding OSE-derived cancer cells will be discussed in the next section. Although the specific roles for purinergic signaling in ovarian physiology are not completely understood, significant advances have been made in deciphering the role of purines in cancer. Plenty of information supports that purinergic system elements have a role in cancer progression, and this implicates that they are potential therapeutic targets.
Purinergic signalling in the nervous system: an overview.
Here we will address the relevance of the purinergic system in ovarian cancer OC. Ovarian cancer OC is considered the most lethal gynecological malignancy, as it is usually diagnosed by the time the tumor has spread to other regions [ 71 ]. OC is the seventh most common type of cancer in women, and patients have a low survival rate [ 72 ]. Early detection of the disease proves difficult due to unspecific symptoms such as abdominal pain and bloating, whereas advanced stages are confused with gastrointestinal illnesses [ 73 ].
According to histological characteristics, epithelial ovarian cancer EOC is classified in serous, endometrioid, and clear cells and in mucinous carcinomas [ 74 ]. Ovarian tumors frequently show disseminated metastasis through ascites in the peritoneal cavity.
OC cells are exfoliated from the primary tumor surface to the peritoneal fluid, where they survive as single cells or multicellular aggregates. These cells acquire resistance to anoikis, have stem cell properties, and are plastic in terms of switching between epithelial and mesenchymal phenotypes. In addition to cancer cells, the malignant ascite microenvironment has normal cell types, such as platelets, associated fibroblast, and immune cells, which support and assist cancer cells [ 75 , 76 ].
This distinctive tumor microenvironment TME has paracrine and autocrine signals that support cancer cell proliferation, death evasion, dissemination, and invasion to peritoneal organs. Therefore, understanding cellular and molecular mechanisms that promote progression of the disease is very relevant. Purinergic signaling has emerged as an important regulator of tumor growth [ 77 ]. The following facts support this assertion: 1 cancer cells increase in metabolic rate [ 78 ]; 2 ATP and ADO levels increase in the tumor interstitium [ 79 , 80 ]; 3 purinergic receptors are expressed in tumor cells [ 77 ]; and 4 high CD73 ectonucleotidase expression is a prognosis factor for several types of cancer [ 81 ].
Furthermore, the biphasic response induced by ATP suggested that these cells could express two types of purinergic receptors: channels operated by ligands and G protein-coupled receptors GPCRs. These findings showed that ATP effects differ across cell lines, which could be associated with the activated intracellular mechanism. P2X7 expression in human ovaries is confined to the OSE, whereas in EOC biopsies, its expression is wider and localized in transformed zones [ 86 , 87 ]. Additionally, receptor functionality was evaluated in cell lines, and it was demonstrated that its stimulation induces ERK and AKT phosphorylation, whereas its inhibition reduces cell viability [ 87 ].
The latter result was surprising due to previous findings that associated P2X7 receptor activation with apoptosis. An important feature of cancer cells is their ability to migrate and invade secondary organs. One process that allows OC cells to dissociate from primary tumors and survive in peritoneal fluid is the EMT, in which cells switch from an epithelial to a mesenchymal phenotype. Even though this process was first described in embryonic development, today its role in cancer is well accepted. The involvement of purines in EMT has recently been reviewed [ 9 ].
Interestingly, addition of apyrase Apy to cell medium, with the aim of removing extracellular ATP, decreased cell migration and favored an epithelial-like phenotype due to the relocation of E-cadherin to SKOV-3 cellular junctions [ 88 ]. The authors concluded that products obtained by ATP hydrolysis i.
Even though extracellular ADO has not been measured in tumors in vivo, there is evidence that ADO levels increase in tumor microdialysates and are more abundant at the core of the tumor [ 79 ]. Correspondingly, ADO function has been evaluated in several types of cancer, and an immunosuppressive role has been proposed for this molecule through ADORA2A receptor activation.
Therefore, strategies such as CD39 and CD73 inhibition with the aim of reducing extracellular ADO concentrations have been performed, and an improved immune response was described using antibodies against these enzymes [ 89 ]. Recent evidence demonstrated that CD73 expression in primary-derived OC promotes stemness and tumor growth and proved that this enzyme acts as an EMT promoter [ 91 ], allowing us to recognize CD73 as a promising target for OC.
Altogether, the evidence highlights purinergic signaling as an important regulator in EOC progression. Since Geoffrey Burnstock proposed his purinergic hypothesis in the early s, enormous advances have been achieved in describing the molecular elements that conform the purinergic system and in our understanding of a complex system that is constituted as a continuous metabolic network together with the dynamic events in extracellular signaling.
Indeed, the specific actions of purinergic signaling in each system are still being discovered, and its study is a growing field of knowledge. In this chapter, we summarize current knowledge of purinergic signaling in the ovary, where an extensive and specialized expression of purinergic receptors and purine-handling enzymes are observed.
The accumulated evidence depicts an emergent and complex system, and at the same time, it raises important questions with deep physiological and pathological implications. The authors declare that there is no conflict of interest regarding the publication of this article. Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution 3. Help us write another book on this subject and reach those readers.
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Purinergic signalling and disorders of the central nervous system | Nature Reviews Drug Discovery
Edited by Gyula Mozsik. We are IntechOpen, the world's leading publisher of Open Access books. Built by scientists, for scientists. Our readership spans scientists, professors, researchers, librarians, and students, as well as business professionals. ATP and adenosine are crucial regulators of mucociliary clearance. In the human skeleton , nearly all P2Y and P2X receptors have been found in osteoblasts and osteoclasts.
These receptors enable the regulation of multiple processes such as cell proliferation, differentiation, function, and death. The other three adenosine receptors are involved in bone formation. In Alzheimer's disease AD , the expression of A1 and A2A receptors in the frontal cortex of the human brain is increased, while the expression of A1 receptors in the outer layers of hippocampal dentate gyrus is decreased. In the airways of patients with asthma , the expression of adenosine receptors is upregulated.
Adenosine receptors affect bronchial reactivity, endothelial permeability, fibrosis, angiogenesis and mucus production. Purinergic signalling is involved in the pathophysiology of several bone and cartilage diseases such as osteoarthritis , rheumatoid arthritis , and osteoporosis. The P2RX7 receptor is overexpressed in most malignant tumors. Formation of foam cells is inhibited by adenosine A2A receptors.
Abnormal levels of ATP and adenosine are present in the airways of patients with chronic obstructive pulmonary disease. The release of ATP increases adenosine levels and activates nitric oxide synthase , both of which induces the relaxation of the corpus cavernosum penis. In male patients with vasculogenic impotence, dysfunctional adenosine A2B receptors are associated with the resistance of the corpus cavernosum to adenosine. On the other hand, excess adenosine in penile tissue contributes to priapism.
Purinergic signalling and disorders of the central nervous system
The bronchoalveolar lavage BAL fluid of patients with idiopathic pulmonary fibrosis contains a higher concentration of ATP than that of control subjects. As a result, the expression of co-stimulatory molecules by APCs is upregulated. Mechanical deformation of the skin by acupuncture needles appears to result in the release of adenosine. Methotrexate , which has strong anti-inflammatory properties, inhibits the action of dihydrofolate reductase , leading to an accumulation of adenosine.
On the other hand, the adenosine-receptor antagonist caffeine reverses the anti-inflammatory effects of methotrexate. Many anti-platelet drugs such as Prasugrel , Ticagrelor , and Ticlopidine are adenosine diphosphate ADP receptor inhibitors.
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Before the expiry of its patent, the P2Y12 receptor antagonist Clopidogrel trade name : Plavix was the second most prescribed drug in the world. Theophylline was originally used as a bronchodilator , although its usage has declined due to several side effects such as seizures and cardiac arrhythmias caused by adenosine A1 receptor antagonism. Several herbs used in Traditional Chinese medicine contain drug compounds that are antagonists of P2X purinoreceptors. Regadenoson , a vasodilator which acts on the adenosine A2A receptor , was approved by the United States Food and Drug Administration in and is currently widely used in the field of cardiology.
Purinergic signalling is an important regulatory mechanism in a wide range of inflammatory diseases. It is understood that shifting the balance between purinergic P1 and P2 signalling is an emerging therapeutic concept that aims to dampen pathologic inflammation and promote healing.
In the s, the classical view of autonomic smooth muscle control was based upon Dale's principle , which asserts that each nerve cell can synthesize, store, and release only one neurotransmitter. It was therefore assumed that a sympathetic neuron releases noradrenaline only, while an antagonistic parasympathetic neuron releases acetylcholine only. Although the concept of cotransmission gradually gained acceptance in the s, the belief that a single neuron acts via a single type of neurotransmitter continued to dominate the field of neurotransmission throughout the s.
Beginning in , Geoffrey Burnstock ignited decades of controversy after he proposed the existence of a non-adrenergic, non-cholinergic NANC neurotransmitter, which he identified as ATP after observing the cellular responses in a number of systems exposed to the presence of cholinergic and adrenergic blockers. Burnstock's proposal was met with criticism, since ATP is an ubiquitous intracellular molecular energy source  so it seemed counter-intuitive that cells might also actively release this vital molecule as a neurotransmitter. After years of prolonged scepticism, however, the concept of purinergic signalling was gradually accepted by the scientific community.
Today, purinergic signalling is no longer considered to be confined to neurotransmission , but is regarded as a general intercellular communication system of many, if not all, tissues. From Wikipedia, the free encyclopedia. Part of a series on Purinergic signalling Simplified illustration of extracellular purinergic signalling.
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