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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 -
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 -
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 -
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 -
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 -
Sub-cellular Biochemistry 2011The current treatments offered to patients with chronic respiratory diseases are being re-evaluated based on the loss of potency during long-term treatments or because... (Review)
Review
The current treatments offered to patients with chronic respiratory diseases are being re-evaluated based on the loss of potency during long-term treatments or because they only provide significant clinical benefits to a subset of the patient population. For instance, glucocorticoids are considered the most effective anti-inflammatory therapies for chronic inflammatory and immune diseases, such as asthma. But they are relatively ineffective in asthmatic smokers, and patients with chronic obstructive pulmonary disease (COPD) or cystic fibrosis (CF). As such, the pharmaceutical industry is exploring new therapeutic approaches to address all major respiratory diseases. The previous chapters demonstrated the widespread influence of purinergic signaling on all pulmonary functions and defense mechanisms. In Chap. 8, we described animal studies which highlighted the critical role of aberrant purinergic activities in the development and maintenance of chronic airway diseases. This last chapter covers all clinical and pharmaceutical applications currently developed based on purinergic receptor agonists and antagonists. We use the information acquired in the previous chapters on purinergic signaling and lung functions to scrutinize the preclinical and clinical data, and to realign the efforts of the pharmaceutical industry.
Topics: Animals; Biomarkers; Epithelial Cells; Humans; Lung Diseases; Molecular Targeted Therapy; Predictive Value of Tests; Purinergic Agonists; Purinergic Antagonists; Purines; Receptors, Purinergic; Respiratory Mucosa; Signal Transduction
PubMed: 21560050
DOI: 10.1007/978-94-007-1217-1_9 -
Neuroscience Bulletin Jun 2009The immunocytes microglia in the central nervous system (CNS) were reported to play a crucial role in neurodegeneration. As a member of P2 receptors family, purinoceptor... (Review)
Review
The immunocytes microglia in the central nervous system (CNS) were reported to play a crucial role in neurodegeneration. As a member of P2 receptors family, purinoceptor P2Y6 has attracted much attention recently. Previous studies showed that purinoceptor P2Y6 mainly contributed to microglia activation and their later phagocytosis in CNS, while in immune system, it participated in the secretion of interleukin (IL)-8 from monocytes and macrocytes. So there raises a question: whether purinoceptor P2Y6 also takes part in neuroinflammation? Thus, this review mainly concerns about the properties and roles of purinoceptor P2Y6, including (1) structure of purinoceptor P2Y6; (2) distribution and properties of purinoceptor P2Y6; (3) relationships between purinoceptor P2Y6 and microglia; (4) relationships between purinoceptor P2Y6 and immunoinflammation. Itos proposed that purinoceptor P2Y6 may play a role in neuroinflammation in CNS, although further research is still required.
Topics: Animals; Humans; Inflammation; Microglia; Monocytes; Phagocytosis; Receptors, Purinergic P2
PubMed: 19448690
DOI: 10.1007/s12264-009-0120-3 -
Purinergic Signalling Dec 2022Within the family of purinergic receptors, the P2X1 receptor is a ligand-gated ion channel that plays a role in urogenital, immune and cardiovascular function.... (Review)
Review
Within the family of purinergic receptors, the P2X1 receptor is a ligand-gated ion channel that plays a role in urogenital, immune and cardiovascular function. Specifically, the P2X1 receptor has been implicated in controlling smooth muscle contractions of the vas deferens and therefore has emerged as an exciting drug target for male contraception. In addition, the P2X1 receptor contributes to smooth muscle contractions of the bladder and is a target to treat bladder dysfunction. Finally, platelets and neutrophils have populations of P2X1 receptors that could be targeted for thrombosis and inflammatory conditions. Drugs that specifically target the P2X1 receptor have been challenging to develop, and only recently have small molecule antagonists of the P2X1 receptor been available. However, these ligands need further biological validation for appropriate selectivity and drug-like properties before they will be suitable for use in preclinical models of disease. Although the atomic structure of the P2X1 receptor has yet to be determined, the recent discovery of several other P2X receptor structures and improvements in the field of structural biology suggests that this is now a distinct possibility. Such efforts may significantly improve drug discovery efforts at the P2X1 receptor.
Topics: Male; Humans; Receptors, Purinergic P2X1; Urinary Bladder; Muscle Contraction; Vas Deferens; Blood Platelets; Receptors, Purinergic P2X; Adenosine Triphosphate
PubMed: 35821454
DOI: 10.1007/s11302-022-09880-4 -
International Journal of Molecular... Nov 2021ATP is stored in millimolar concentrations within the intracellular medium but may be released to extracellular sites either through the damaged plasma membrane or by...
ATP is stored in millimolar concentrations within the intracellular medium but may be released to extracellular sites either through the damaged plasma membrane or by means of various transporters [...].
Topics: Animals; Humans; Neuroinflammatory Diseases; Purines; Receptors, Purinergic; Signal Transduction
PubMed: 34884700
DOI: 10.3390/ijms222312895