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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 -
Cell Apr 2020Sensory neurons initiate defensive reflexes that ensure airway integrity. Dysfunction of laryngeal neurons is life-threatening, causing pulmonary aspiration, dysphagia,...
Sensory neurons initiate defensive reflexes that ensure airway integrity. Dysfunction of laryngeal neurons is life-threatening, causing pulmonary aspiration, dysphagia, and choking, yet relevant sensory pathways remain poorly understood. Here, we discover rare throat-innervating neurons (∼100 neurons/mouse) that guard the airways against assault. We used genetic tools that broadly cover a vagal/glossopharyngeal sensory neuron atlas to map, ablate, and control specific afferent populations. Optogenetic activation of vagal P2RY1 neurons evokes a coordinated airway defense program-apnea, vocal fold adduction, swallowing, and expiratory reflexes. Ablation of vagal P2RY1 neurons eliminates protective responses to laryngeal water and acid challenge. Anatomical mapping revealed numerous laryngeal terminal types, with P2RY1 neurons forming corpuscular endings that appose laryngeal taste buds. Epithelial cells are primary airway sentinels that communicate with second-order P2RY1 neurons through ATP. These findings provide mechanistic insights into airway defense and a general molecular/genetic roadmap for internal organ sensation by the vagus nerve.
Topics: Afferent Pathways; Animals; Female; Gene Expression Regulation; Glossopharyngeal Nerve; Larynx; Male; Mice; Mice, Inbred C57BL; Pharynx; Receptors, Purinergic P2Y1; Sensory Receptor Cells; Vagus Nerve
PubMed: 32259485
DOI: 10.1016/j.cell.2020.03.004 -
The Journal of Experimental Medicine Mar 2022Microglia, the main immunocompetent cells of the brain, regulate neuronal function, but their contribution to cerebral blood flow (CBF) regulation has remained elusive....
Microglia, the main immunocompetent cells of the brain, regulate neuronal function, but their contribution to cerebral blood flow (CBF) regulation has remained elusive. Here, we identify microglia as important modulators of CBF both under physiological conditions and during hypoperfusion. Microglia establish direct, dynamic purinergic contacts with cells in the neurovascular unit that shape CBF in both mice and humans. Surprisingly, the absence of microglia or blockade of microglial P2Y12 receptor (P2Y12R) substantially impairs neurovascular coupling in mice, which is reiterated by chemogenetically induced microglial dysfunction associated with impaired ATP sensitivity. Hypercapnia induces rapid microglial calcium changes, P2Y12R-mediated formation of perivascular phylopodia, and microglial adenosine production, while depletion of microglia reduces brain pH and impairs hypercapnia-induced vasodilation. Microglial actions modulate vascular cyclic GMP levels but are partially independent of nitric oxide. Finally, microglial dysfunction markedly impairs P2Y12R-mediated cerebrovascular adaptation to common carotid artery occlusion resulting in hypoperfusion. Thus, our data reveal a previously unrecognized role for microglia in CBF regulation, with broad implications for common neurological diseases.
Topics: Adult; Aged; Animals; Brain; Calcium Signaling; Carotid Artery Diseases; Cerebrovascular Circulation; Evoked Potentials; Female; Humans; Hypercapnia; Male; Mice; Mice, Inbred C57BL; Mice, Transgenic; Microglia; Neurovascular Coupling; Receptors, Purinergic; Receptors, Purinergic P2Y12; Vasodilation; Vibrissae
PubMed: 35201268
DOI: 10.1084/jem.20211071 -
Autonomic Neuroscience : Basic &... Jan 2022The story of purinergic neurotransmission and regulation is intimately linked to studies of the somatosensory system. Burnstock's contributions to the discovery of ATP... (Review)
Review
The story of purinergic neurotransmission and regulation is intimately linked to studies of the somatosensory system. Burnstock's contributions to the discovery of ATP as a primary afferent neurotransmitter, as well as a signal of peripheral tissue damage that depolarised sensory neurons initiated a new period of pain research. The neuro-immune interactions that occur after tissue damage and are important for pain have now also been found to involve purinergic signalling, and adenosine has been demonstrated to have significant analgesic effects. In the pain field as in so many other areas of neuroscience and physiology, Burnstock's contributions have been critical to the expansion of our knowledge about the significance of purines. His mechanistic insights have profound significance for understanding the pain system and further underscore his stature as a pioneer and force for progress in biomedicine.
Topics: Adenosine Triphosphate; Humans; Pain; Purines; Receptors, Purinergic; Signal Transduction; Synaptic Transmission
PubMed: 34773738
DOI: 10.1016/j.autneu.2021.102902 -
International Journal of Molecular... Jun 2023Extensive evidence indicates that the activation of the P2X receptor (P2XR), an ATP-gated ion channel highly expressed in immune and brain cells, is strictly associated... (Review)
Review
Extensive evidence indicates that the activation of the P2X receptor (P2XR), an ATP-gated ion channel highly expressed in immune and brain cells, is strictly associated with the release of extracellular vesicles. Through this process, P2XR-expressing cells regulate non-classical protein secretion and transfer bioactive components to other cells, including misfolded proteins, participating in inflammatory and neurodegenerative diseases. In this review, we summarize and discuss the studies addressing the impact of P2XR activation on extracellular vesicle release and their activities.
Topics: Brain; Extracellular Vesicles; Receptors, Purinergic P2X7; Adenosine Triphosphate
PubMed: 37372953
DOI: 10.3390/ijms24129805 -
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 -
Biochemical Pharmacology May 2021Extracellular purine and pyrimidine nucleotides produce their pharmacological effects through P2 receptors. These were first named by Geoff Burnstock in an extensive... (Review)
Review
Extracellular purine and pyrimidine nucleotides produce their pharmacological effects through P2 receptors. These were first named by Geoff Burnstock in an extensive review in 1978. They were then subdivided into P and P purinoceptors by Burnstock and Kennedy in 1985, based on applying pharmacological criteria to data generated by functional studies in smooth muscle tissues. Several other P2 subtypes, P, P, P and P were subsequently identified in the following years, again using pharmacological criteria. The number and identity of subtypes were clarified and simplified by the cloning of seven ATP-sensitive ligand-gated ion channel subunits and eight adenine and/or uracil nucleotide-sensitive G protein-coupled receptors from 1993 onwards. The former were all classified as members of the P2X receptor family and the latter as members of the P2Y receptor family. More recently, high resolution imaging of the tertiary and quaternary structures of several P2X and P2Y receptor subtypes has provided a much greater understanding of how and where agonists and antagonists bind to the receptors and how this leads to changes in receptor conformation and activity. In addition, medicinal chemistry has produced a variety of subtype-selective agonists and antagonists, some of which are now in clinical use. This progress and success is a testimony to the foresight, intelligence, enthusiasm and drive of Geoff Burnstock, who led the field forward throughout his scientific life.
Topics: Adenosine Triphosphate; Animals; Humans; Purinergic P2X Receptor Agonists; Purinergic P2X Receptor Antagonists; Purinergic P2Y Receptor Agonists; Purinergic P2Y Receptor Antagonists; Receptors, Purinergic P2X; Receptors, Purinergic P2Y; Signal Transduction
PubMed: 33444568
DOI: 10.1016/j.bcp.2021.114408 -
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