-
Purinergic Signalling Mar 2023The neurotrophin brain-derived neurotrophic factor (BDNF), which acts as a transducer, is responsible for improving cerebral stroke, neuropathic pain, and depression.... (Review)
Review
The neurotrophin brain-derived neurotrophic factor (BDNF), which acts as a transducer, is responsible for improving cerebral stroke, neuropathic pain, and depression. Exercise can alter extracellular nucleotide levels and purinergic receptors in central nervous system (CNS) structures. This inevitably activates or inhibits the expression of BDNF via purinergic receptors, particularly the P2X receptor (P2XR), to alleviate pathological progression. In addition, the significant involvement of sensitive P2X4R in mediating increased BDNF and p38-MAPK for intracerebral hemorrhage and pain hypersensitivity has been reported. Moreover, archetypal P2X7R blockade induces mouse antidepressant-like behavior and analgesia by BDNF release. This review summarizes BDNF-mediated neural effects via purinergic receptors, speculates that P2X4R and P2X7R could be priming molecules in exercise-mediated changes in BDNF, and provides strategies for the protective mechanism of exercise in neurogenic disease.
Topics: Animals; Mice; Antidepressive Agents; Brain-Derived Neurotrophic Factor; Neuralgia; Neuroprotection; Receptors, Purinergic P2X4; Stroke; Receptors, Purinergic P2X7
PubMed: 35821455
DOI: 10.1007/s11302-022-09879-x -
Purinergic Signalling Mar 2023Atherosclerosis is the main pathological basis of cardiovascular disease and involves damage to vascular endothelial cells (ECs) that results in endothelial dysfunction... (Review)
Review
Atherosclerosis is the main pathological basis of cardiovascular disease and involves damage to vascular endothelial cells (ECs) that results in endothelial dysfunction (ED). The vascular endothelium is the key to maintaining blood vessel health and homeostasis. ED is a complex pathological process involving inflammation, shear stress, vascular tone, adhesion of leukocytes to ECs, and platelet aggregation. The activation of P2X4, P2X7, and P2Y2 receptors regulates vascular tone in response to shear stress, while activation of the A2A, P2X4, P2X7, P2Y1, P2Y2, P2Y6, and P2Y12 receptors promotes the secretion of inflammatory cytokines. Finally, P2X1, P2Y1, and P2Y12 receptor activation regulates platelet activity. These purinergic receptors mediate ED and participate in atherosclerosis. In short, P2X4, P2X7, P2Y1, and P2Y12 receptors are potential therapeutic targets for atherosclerosis.
Topics: Humans; Receptors, Purinergic P2; Endothelial Cells; Receptors, Purinergic; Endothelium, Vascular; Atherosclerosis; Receptors, Purinergic P2Y1
PubMed: 34981330
DOI: 10.1007/s11302-021-09839-x -
Purinergic Signalling Mar 2021Development of science needs the cooperation of many creative brains. Sometimes, ideas on a specific area get suddenly exhausted and then it is the time for a privileged... (Review)
Review
Development of science needs the cooperation of many creative brains. Sometimes, ideas on a specific area get suddenly exhausted and then it is the time for a privileged mind to think in a different way and reach the turning point to introduce a new paradigm. This happened to Geoffrey Burnstock, a heterodox thinker and nonconformist scientist that has been the paladin of purinergic signalling since 1972, opening neuroscience to the understanding of organs and tissues functioning and development of a new pharmacology. This review summarizes the contribution of our group to the understanding of the role of the diadenosine polyphosphates, ApA, as signalling molecules, describing their tissue and organ distribution, their transport and storage in secretory vesicles and their release and interaction with purinergic receptors. We also have to acknowledge the friendly and kindly support of Professor Burnstock that showed a great interest in the field from our initial findings and actively stimulated our efforts to establish the extracellular roles and biological significance of these dinucleotides.
Topics: Animals; Dinucleoside Phosphates; Humans; Receptors, Purinergic; Secretory Vesicles; Synapses
PubMed: 33025428
DOI: 10.1007/s11302-020-09736-9 -
Autonomic Neuroscience : Basic &... Sep 2015Adenosine-5'-triphosphate is released by neuroendocrine, endocrine, and other cell types and acts as an extracellular agonist for ligand-gated P2X cationic channels and... (Review)
Review
Adenosine-5'-triphosphate is released by neuroendocrine, endocrine, and other cell types and acts as an extracellular agonist for ligand-gated P2X cationic channels and G protein-coupled P2Y receptors in numerous organs and tissues, including the endocrine system. The breakdown of ATP by ectonucleotidases not only terminates its extracellular messenger functions, but also provides a pathway for the generation of two additional agonists: adenosine 5'-diphosphate, acting via some P2Y receptors, and adenosine, a native agonist for G protein-coupled adenosine receptors, also expressed in the endocrine system. This article provides a review of purinergic signaling pathways in the hypothalamic magnocellular neurosecretory cells and neurohypophysis, hypothalamic parvocellular neuroendocrine system, adenohypophysis, and effector glands organized in five axes: hypothalamic-pituitary-gonadal, hypothalamic-pituitary-thyroid, hypothalamic-pituitary-adrenal, hypothalamic-pituitary-growth hormone, and hypothalamic-pituitary-prolactin. We attempted to summarize current knowledge of purinergic receptor subtypes expressed in the endocrine system, including their roles in intracellular signaling, hormone secretion, and other cell functions. We also briefly review the release mechanism for adenosine-5'-triphosphate by neuroendocrine, endocrine and surrounding cells, the enzymes involved in adenosine-5'-triphosphate hydrolysis to adenosine-5'-diphosphate and adenosine, and the relevance of this pathway for sequential activation of receptors and termination of signaling.
Topics: Animals; Endocrine System; Humans; Receptors, Purinergic
PubMed: 25960051
DOI: 10.1016/j.autneu.2015.04.010 -
Biomedical Journal Oct 2017Extracellular nucleotides have been recognized as important mediators of activation, triggering multiple responses via plasma membrane receptors known as P2 receptors.... (Review)
Review
Extracellular nucleotides have been recognized as important mediators of activation, triggering multiple responses via plasma membrane receptors known as P2 receptors. P2 receptors comprise P2X ionotropic receptors and G protein-coupled P2Y receptors. P2X receptors are expressed in many tissues, where they are involved in a number of functions including synaptic transmission, muscle contraction, platelet aggregation, inflammation, macrophage activation, differentiation and proliferation, neuropathic and inflammatory pain. P2X4 is one of the most sensitive purinergic receptors (at nanomolar ATP concentrations), about one thousand times more than the archetypal P2X7. P2X4 is widely expressed in central and peripheral neurons, in microglia, and also found in various epithelial tissues and endothelial cells. It localizes on the plasma membrane, but also in intracellular compartments. P2X4 is preferentially localized in lysosomes, where it is protected from proteolysis by its glycosylation. High ATP concentration in the lysosomes does not activate P2X4 at low pH; P2X4 gets activated by intra-lysosomal ATP only in its fully dissociated tetra-anionic form, when the pH increases to 7.4. Thus, P2X4 is functioning as a Ca-channel after the fusion of late endosomes and lysosomes. P2X4 modulates major neurotransmitter systems and regulates alcohol-induced responses in microglia. P2X4 is one of the key receptors mediating neuropathic pain. However, injury-induced upregulation of P2X4 expression is gender dependent and plays a key role in pain difference between males and females. P2X4 is also involved in inflammation. Extracellular ATP being a pro-inflammatory molecule, P2X4 can trigger inflammation in response to high ATP release. It is therefore involved in multiple pathologies, like post-ischemic inflammation, rheumatoid arthritis, airways inflammation in asthma, neurodegenerative diseases and even metabolic syndrome. Although P2X4 remains poorly characterized, more studies are needed as it is likely to be a potential therapeutic target in these multiple pathologies.
Topics: Adenosine Triphosphate; Animals; Humans; Lysosomes; Microglia; Receptors, Purinergic; Receptors, Purinergic P2X4; Receptors, Purinergic P2X7
PubMed: 29179879
DOI: 10.1016/j.bj.2017.06.010 -
Cancer Research Nov 2012Purines were long thought to be restricted to the intracellular compartment, where they are used for energy transactions, nucleic acid synthesis, and a multiplicity of... (Review)
Review
Purines were long thought to be restricted to the intracellular compartment, where they are used for energy transactions, nucleic acid synthesis, and a multiplicity of biochemical reactions. However, it is now clear that both adenosine and adenosine triphosphate are (i) abundant biochemical components of the tumor microenvironment, (ii) potent modulators of immune cell responses and cytokine release, and (iii) key players in host-tumor interaction. Moreover, both ATP and adenosine directly affect tumor cell growth. Adenosine is a powerful immunosuppressant (mainly acting at A2A receptors) and a modulator of cell growth (mainly acting at A3 receptors). ATP is a proinflammatory (acting at P2Y1, P2Y2, P2Y4, P2Y6, and P2Y12, and at P2X4 and P2X7 receptors), an immunosuppressant (acting at P2Y11), and a growth-promoting agent (acting at P2Y1, P2Y2, and P2X7 receptors). This complex signaling network generates an array of inhibitory and stimulatory responses that affect immune cell function, tumor growth, and metastatic dissemination. Investigation of purinergic signaling has increased our understanding of the tumor microenvironment and opened new and exciting avenues for the development of novel therapeutics.
Topics: Animals; Humans; Neoplasms; Purines; Receptors, Purinergic
PubMed: 23090120
DOI: 10.1158/0008-5472.CAN-12-1600 -
Current Opinion in Pharmacology Dec 2012Extracellular purines play important roles as neurotransmitters and paracrine mediators in the gastrointestinal (GI) tract. Inflammation of the GI tract causes marked... (Review)
Review
Extracellular purines play important roles as neurotransmitters and paracrine mediators in the gastrointestinal (GI) tract. Inflammation of the GI tract causes marked changes in the release and extracellular catabolism of purines, and can modulate purinoceptor expression and/or signaling. The functional consequences of this include suppression of the purinergic component of inhibitory neuromuscular and neurovascular transmission, increased release of purines from immune and epithelial cells, loss of enteric neurons to damage through P2X(7) purinoceptors, and enhanced activation of pain fibres. The purinergic system represents an important target for drug therapies that may improve GI inflammation and its consequences.
Topics: Animals; Gastrointestinal Diseases; Gastrointestinal Tract; Humans; Inflammation; Molecular Targeted Therapy; Neurons; Paracrine Communication; Purines; Receptors, Purinergic; Receptors, Purinergic P2X7; Signal Transduction
PubMed: 23063457
DOI: 10.1016/j.coph.2012.09.011 -
Molecules (Basel, Switzerland) Mar 2022Pain is an essential modality of sensation in the body. Purinergic signaling plays an important role in nociceptive pain transmission, under both physiological and... (Review)
Review
Pain is an essential modality of sensation in the body. Purinergic signaling plays an important role in nociceptive pain transmission, under both physiological and pathophysiological conditions, and is important for communication between both neuronal and non-neuronal cells. Microglia and astrocytes express a variety of purinergic effectors, and a variety of receptors play critical roles in the pathogenesis of neuropathic pain. In this review, we discuss our current knowledge of purinergic signaling and of the compounds that modulate purinergic transmission, with the aim of highlighting the importance of purinergic pathways as targets for the treatment of persistent pain.
Topics: Humans; Microglia; Neuralgia; Neurons; Receptors, Purinergic; Signal Transduction
PubMed: 35335282
DOI: 10.3390/molecules27061919 -
Purinergic Signalling Mar 2021The international purinergic scientific community has lost its pioneer. Geoffrey Burnstock, born on the 10th of May 1929 in London, died on the 2nd of June 2020, aged... (Review)
Review
The international purinergic scientific community has lost its pioneer. Geoffrey Burnstock, born on the 10th of May 1929 in London, died on the 2nd of June 2020, aged 91, in Melbourne (Australia). Geoff was one of the most highly regarded scientists of his generation. In the 1960s and 1970s, he developed a radical and somehow heretical new theory and opened an entire new field of science, signalling via extracellular nucleotides (the "purinergic theory"), which revolutionized our understanding of how cells communicate between each other. Initially, his unconventional theory found a lot of resistance in the scientific community. Once, one scientist even threatened to devote his entire life to disproving Burnstock's theory. Undeterred, Geoff went further on, and continued to accumulate evidence in favour of his hypothesis, and led the field ever since. He struggled to attract new scientists to this new field of research and, in the early 1990s, due to new molecular biology techniques making it possible to isolate and identify cell surface receptors for ATP and its breakdown product adenosine, did evidence emerge that eventually convinced the doubters. The number of spontaneous obituaries and messages honouring Geoff's memory that have appeared on specialized Journals and in the public press throughout the world since last June indicates that many people are clearly affected by his death. Besides being a rigorous, ethical and extremely brilliant scientist, Geoff was an extraordinary human being, always eager to collaborate and share data, never jealous of his findings and capable of learning things even from young people. He was known for his enthusiasm, empathy and ability to motivate young scientists and promote their careers. After the establishment of the Purine Club back in the 1990s, numerous Purine Club Chapters have been formed around the world with Geoff's help and encouragement. He has obviously also been the inspirator and founder of our Journal, Purinergic Signalling (PUSI). For this reason, Charles Kennedy, the current Editor of the Journal, and myself thought that it might be nice to invite representatives from all known Purine Clubs to send a few notes to be published in PUSI on the history of their club and how Geoff inspired, aided or supported them. Here, I have collected all their contributions and I share with the entire purinergic community my personal memories on how the Purine Club was born and developed thanks to the invaluable mentoring of Geoffrey Burnstock. I apologize in advance if I am missing some information or forgot to mention somebody, and I strongly encourage all readers to submit memories and additional information that I shall gather for future writing. Keeping alive the history of how the field developed will be the best tribute that we can play to celebrate Geoff's work along the years.
Topics: Congresses as Topic; Humans; Purines; Receptors, Purinergic; Signal Transduction
PubMed: 33165707
DOI: 10.1007/s11302-020-09749-4 -
Trends in Endocrinology and Metabolism:... Nov 2009The hypothalamus controls the release of hormones by the pituitary and is involved in control of food and water intake, sexual behavior, reproduction and daily cycles in... (Review)
Review
The hypothalamus controls the release of hormones by the pituitary and is involved in control of food and water intake, sexual behavior, reproduction and daily cycles in physiological state and behavior, temperature regulation and emotional responses. Adenosine-5'-triphosphate (ATP) and its metabolic products contribute to these functions, acting as agonists for adenosine and P2Y receptors and two-transmembrane domain P2X receptor channels. This review summarizes the recent findings on purinergic receptor expression and their roles in signaling and cellular function in secretory and supporting cells of the hypothalamopituitary system. ATP secretion by these tissues, the enzymes involved in ATP hydrolysis, and the relevance of this pathway for sequential activation of receptors and termination of signaling are also discussed.
Topics: Adenosine Triphosphate; Animals; Humans; Hypothalamo-Hypophyseal System; Models, Biological; Pituitary-Adrenal System; Receptors, Purinergic; Signal Transduction
PubMed: 19800813
DOI: 10.1016/j.tem.2009.05.005