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Journal of Thrombosis and Haemostasis :... Jun 2015The platelet P2Y12 receptor (P2Y12R) for adenosine 5'diphosphate (ADP) plays a central role in platelet function, hemostasis, and thrombosis. Patients with inherited... (Review)
Review
The platelet P2Y12 receptor (P2Y12R) for adenosine 5'diphosphate (ADP) plays a central role in platelet function, hemostasis, and thrombosis. Patients with inherited P2Y12R defects display mild-to-moderate bleeding diatheses. Defects of P2Y12R should be suspected when ADP, even at high concentrations (≥ 10 μm), is unable to induce full, irreversible platelet aggregation. P2Y12R also plays a role in inflammation: its role in the pathogenesis of allergic asthma has been well characterized. In addition, inhibition or genetic deficiency of P2Y12R has antitumor effects. Drugs inhibiting P2Y12R are potent antithrombotic drugs. Clopidogrel is the P2Y12R antagonist that is most widely used in the clinical setting. Its most important drawback is its inability to inhibit adequately P2Y12R-dependent platelet function in about one-third of patients. New drugs, such as prasugrel and ticagrelor, which effectively inhibit P2Y12R in the vast majority of patients, have proved to be more efficacious than clopdidogrel in preventing major adverse cardiovascular events.
Topics: Adenosine Diphosphate; Animals; Blood Platelets; Cardiovascular Diseases; Fibrinolytic Agents; Hemorrhage; Humans; Platelet Aggregation Inhibitors; Protein Conformation; Purinergic P2Y Receptor Antagonists; Receptors, Purinergic P2Y12; Signal Transduction; Structure-Activity Relationship
PubMed: 26149010
DOI: 10.1111/jth.12952 -
Annual Review of Immunology Apr 2019ATP, NAD, and nucleic acids are abundant purines that, in addition to having critical intracellular functions, have evolved extracellular roles as danger signals... (Review)
Review
ATP, NAD, and nucleic acids are abundant purines that, in addition to having critical intracellular functions, have evolved extracellular roles as danger signals released in response to cell lysis, apoptosis, degranulation, or membrane pore formation. In general ATP and NAD have excitatory and adenosine has anti-inflammatory effects on immune cells. This review focuses on recent advances in our understanding of purine release mechanisms, ectoenzymes that metabolize purines (CD38, CD39, CD73, ENPP1, and ENPP2/autotaxin), and signaling by key P2 purinergic receptors (P2X7, P2Y2, and P2Y12). In addition to metabolizing ATP or NAD, some purinergic ectoenzymes metabolize other inflammatory modulators, notably lysophosphatidic acid and cyclic GMP-AMP (cGAMP). Also discussed are extracellular signaling effects of NAD mediated by ADP-ribosylation, and epigenetic effects of intracellular adenosine mediated by modification of -adenosylmethionine-dependent DNA methylation.
Topics: ADP-Ribosylation; Adenosine Triphosphate; Animals; DNA Methylation; Humans; Inflammation; Lysophospholipids; Purines; Receptors, Purinergic; Signal Transduction
PubMed: 30676821
DOI: 10.1146/annurev-immunol-051116-052406 -
Signal Transduction and Targeted Therapy Apr 2021Purines and their derivatives, most notably adenosine and ATP, are the key molecules controlling intracellular energy homoeostasis and nucleotide synthesis. Besides,... (Review)
Review
Purines and their derivatives, most notably adenosine and ATP, are the key molecules controlling intracellular energy homoeostasis and nucleotide synthesis. Besides, these purines support, as chemical messengers, purinergic transmission throughout tissues and species. Purines act as endogenous ligands that bind to and activate plasmalemmal purinoceptors, which mediate extracellular communication referred to as "purinergic signalling". Purinergic signalling is cross-linked with other transmitter networks to coordinate numerous aspects of cell behaviour such as proliferation, differentiation, migration, apoptosis and other physiological processes critical for the proper function of organisms. Pathological deregulation of purinergic signalling contributes to various diseases including neurodegeneration, rheumatic immune diseases, inflammation, and cancer. Particularly, gout is one of the most prevalent purine-related disease caused by purine metabolism disorder and consequent hyperuricemia. Compelling evidence indicates that purinoceptors are potential therapeutic targets, with specific purinergic agonists and antagonists demonstrating prominent therapeutic potential. Furthermore, dietary and herbal interventions help to restore and balance purine metabolism, thus addressing the importance of a healthy lifestyle in the prevention and relief of human disorders. Profound understanding of molecular mechanisms of purinergic signalling provides new and exciting insights into the treatment of human diseases.
Topics: Apoptosis; Cell Communication; Humans; Metabolic Diseases; Purines; Receptors, Purinergic; Signal Transduction
PubMed: 33907179
DOI: 10.1038/s41392-021-00553-z -
Neurobiology of Disease Sep 2023Purinergic receptors (Rs) of the ATP/ADP, UTP/UDP (P2X, P2Y) and adenosine (A1, A2A)-sensitive classes broadly interfere with cognitive processes both under quasi normal... (Review)
Review
Purinergic receptors (Rs) of the ATP/ADP, UTP/UDP (P2X, P2Y) and adenosine (A1, A2A)-sensitive classes broadly interfere with cognitive processes both under quasi normal and disease conditions. During neurodegenerative illnesses, high concentrations of ATP are released from the damaged neuronal and non-neuronal cells of the brain; then, this ATP is enzymatically degraded to adenosine. Thus, the primary injury in neurodegenerative diseases appears to be caused by various protein aggregates on which a superimposed damage mediated by especially P2X7 and A2AR activation develops; this can be efficiently prevented by small molecular antagonists in animal models of the above diseases, or are mitigated in the respective knockout mice. Dementia is a leading symptom in Alzheimer's disease (AD), and accompanies Parkinson's disease (PD) and Huntington's disease (HD), especially in the advanced states of these illnesses. Animal experimentation suggests that P2X7 and A2ARs are also involved in a number of psychiatric diseases, such as major depressive disorder (MDD), obsessive compulsive behavior, and attention deficit hyperactivity disorder. In conclusion, small molecular antagonists of purinergic receptors are expected to supply us in the future with pharmaceuticals which are able to combat in a range of neurological/psychiatric diseases the accompanying cognitive deterioration.
Topics: Animals; Mice; Depressive Disorder, Major; Receptors, Purinergic; Adenosine; Adenosine Triphosphate; Nervous System Diseases; Cognition
PubMed: 37453562
DOI: 10.1016/j.nbd.2023.106229 -
Neuropharmacology Dec 2022Major depressive disorder (MDD) is one of the most prevalent psychiatric illnesses worldwide which impairs the social functioning of the afflicted patients. Astrocytes... (Review)
Review
Major depressive disorder (MDD) is one of the most prevalent psychiatric illnesses worldwide which impairs the social functioning of the afflicted patients. Astrocytes promote homeostasis of the CNS and provide defense against various types of harmful influences. Increasing evidence suggests that the number, morphology and function of astrocytes are deteriorated in the depressed brain and the malfunction of the astrocytic purinergic system appears to participate in the pathophysiology of MDD. Adenosine 5'-triphosphate (ATP) released from astrocytes modulates depressive-like behavior in animal models and probably also clinical depression in patients. Astrocytes possess purinergic receptors, such as adenosine A receptors (Rs), and P2X7, P2Y, and P2YRs, which mediate neuroinflammation, neuro(glio)transmission, and synaptic plasticity in depression-relevant areas of the brain (e.g. medial prefrontal cortex, hippocampus, amygdala nuclei). By contrast, astrocytic ARs are neuroprotective and immunosuppressive. In the present review, we shall discuss the release of purines from astrocytes, and the expression/function of astrocytic purinergic receptors. Subsequently, we shall review in more detail novel evidence indicating that the dysregulation of astrocytic purinergic signaling actively contributes to the pathophysiology of depression and shall discuss possible therapeutic options based on knowledge recently acquired in this field.
Topics: Adenosine; Adenosine Triphosphate; Animals; Astrocytes; Depression; Depressive Disorder, Major; Receptors, Purinergic; Receptors, Purinergic P2X7
PubMed: 36122663
DOI: 10.1016/j.neuropharm.2022.109252 -
Frontiers in Endocrinology 2022Adenosine triphosphate (ATP) serves as the essential source of cellular energy. Over the last two decades, however, ATP has also attracted increasing interest as an... (Review)
Review
Adenosine triphosphate (ATP) serves as the essential source of cellular energy. Over the last two decades, however, ATP has also attracted increasing interest as an extracellular signal that activates purinergic plasma membrane receptors of the P2 family. P2 receptors are divided into two types: ATP-gated nonselective cation channels (P2X) and G protein-coupled receptors (P2Y), the latter being activated by a broad range of purine and pyrimidine nucleotides (ATP, ADP, UTP, and UDP, among others). Purinergic signaling mechanisms are involved in numerous physiological events and pathophysiological conditions. Here, we address the growing body of evidence implicating purinergic signaling in male reproductive system functions. The life-long generation of fertile male germ cells is a highly complex, yet mechanistically poorly understood process. Given the relatively sparse innervation of the testis, spermatogenesis relies on both endocrine control and multi-directional paracrine communication. Therefore, a detailed understanding of such paracrine messengers, including ATP, is crucial to gain mechanistic insight into male reproduction..
Topics: Adenosine Triphosphate; Endocrine System; Humans; Male; Receptors, Purinergic; Signal Transduction; Spermatogenesis
PubMed: 35480481
DOI: 10.3389/fendo.2022.867011 -
Physiological Research Jul 2020Proper renal blood flow (RBF) and glomerular filtration rate (GFR) are critical for maintaining normal blood pressure, kidney function and water and electrolyte... (Review)
Review
Proper renal blood flow (RBF) and glomerular filtration rate (GFR) are critical for maintaining normal blood pressure, kidney function and water and electrolyte homeostasis. The renal microvasculature expresses a multitude of receptors mediating vasodilation and vasoconstriction, which can influence glomerular blood flow and capillary pressure. Despite this, RBF and GFR remain quite stable when arterial pressure fluctuates because of the autoregulatory mechanism. ATP and adenosine participate in autoregulatory control of RBF and GFR via activation of two different purinoceptor families (P1 and P2). Purinoceptors are widely expressed in renal microvasculature and tubules. Emerging data show altered purinoceptor signaling in hypertension-associated kidney injury, diabetic nephropathy, sepsis, ischemia-reperfusion induced acute kidney injury and polycystic kidney disease. In this brief review, we highlight recent studies and new insights on purinoceptors regulating renal microvascular function and renal hemodynamics. We also address the mechanisms underlying renal microvascular injury and impaired renal autoregulation, focusing on purinoceptor signaling and hypertension-induced renal microvascular dysfunction. Interested readers are directed to several excellent and comprehensive reviews that recently covered the topics of renal autoregulation, and nucleotides in kidney function under physiological and pathophysiological conditions (Inscho 2009, Navar et al. 2008, Carlstrom et al. 2015, Vallon et al. 2020).
Topics: Animals; Glomerular Filtration Rate; Homeostasis; Humans; Hypertension; Kidney; Receptors, Purinergic; Renal Circulation
PubMed: 32301620
DOI: 10.33549/physiolres.934463 -
Purinergic Signalling Sep 2021Purinergic signaling plays a pivotal role in physiological processes and pathological conditions. Over the past decades, conventional pharmacological, biochemical, and... (Review)
Review
Purinergic signaling plays a pivotal role in physiological processes and pathological conditions. Over the past decades, conventional pharmacological, biochemical, and molecular biology techniques have been utilized to investigate purinergic signaling cascades. However, none of them is capable of spatially and temporally manipulating purinergic signaling cascades. Currently, optical approaches, including optopharmacology and optogenetic, enable controlling purinergic signaling with low invasiveness and high spatiotemporal precision. In this mini-review, we discuss optical approaches for controlling purinergic signaling and their applications in basic and translational science.
Topics: Adenosine Triphosphate; Animals; Humans; Optogenetics; Photolysis; Receptors, Purinergic; Signal Transduction
PubMed: 34156578
DOI: 10.1007/s11302-021-09799-2 -
Frontiers in Endocrinology 2021Extracellular nucleosides and nucleotides activate a group of G protein-coupled receptors (GPCRs) known as purinergic receptors, comprising adenosine and P2Y receptors.... (Review)
Review
Extracellular nucleosides and nucleotides activate a group of G protein-coupled receptors (GPCRs) known as purinergic receptors, comprising adenosine and P2Y receptors. Furthermore, purinergic P2X ion channels are activated by ATP. These receptors are expressed in liver resident cells and play a critical role in maintaining liver function. In the normal physiology, these receptors regulate hepatic metabolic processes such as insulin responsiveness, glycogen and lipid metabolism, and bile secretion. In disease states, ATP and other nucleotides serve as danger signals and modulate purinergic responses in the cells. Recent studies have demonstrated that purinergic receptors play a significant role in the development of metabolic syndrome associated non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), fibrosis, hepatocellular carcinoma (HCC) and liver inflammation. In this concise review, we dissect the role of purinergic signaling in different liver resident cells involved in maintaining healthy liver function and in the development of the above-mentioned liver pathologies. Moreover, we discuss potential therapeutic strategies for liver diseases by targeting adenosine, P2Y and P2X receptors.
Topics: Adenosine; Animals; Humans; Liver Diseases; Receptors, Purinergic P2X; Receptors, Purinergic P2Y; Signal Transduction
PubMed: 34456873
DOI: 10.3389/fendo.2021.718429 -
Pharmacology & Therapeutics Aug 2021Purinergic signaling involves the actions of purine nucleotides and nucleosides (such as adenosine) at P1 (adenosine), P2X, and P2Y receptors. Here, we present recent... (Review)
Review
Purinergic signaling involves the actions of purine nucleotides and nucleosides (such as adenosine) at P1 (adenosine), P2X, and P2Y receptors. Here, we present recent data contributing to a comprehensive overview of the association between purinergic signaling and depression. We start with background information on adenosine production and metabolism, followed by a detailed characterization of P1 and P2 receptors, with an emphasis on their expression and function in the brain as well as on their ligands. We provide data suggestive of altered metabolism of adenosine in depressed patients, which might be regarded as a disease biomarker. We then turn to considerable amount of preclinical/behavioral data obtained with the aid of the forced swim test, tail suspension test, learned helplessness model, or unpredictable chronic mild stress model and genetic activation/inactivation of P1 or P2 receptors as well as nonselective or selective ligands of P1 or P2 receptors. We also aimed to discuss the reason underlying discrepancies observed in such studies.
Topics: Depressive Disorder; Humans; Receptors, Purinergic; Signal Transduction
PubMed: 33607148
DOI: 10.1016/j.pharmthera.2021.107821