scholarly journals Purine and purinergic receptors

2018 ◽  
Vol 2 ◽  
pp. 239821281881749 ◽  
Author(s):  
Geoffrey Burnstock
Keyword(s):  
Therapeutic Potential ◽  
P2y Receptors ◽  
Purinergic Signalling ◽  
Breakdown Product ◽  
Pyrimidine Nucleotides ◽  
Signalling Molecule ◽  
Wide Range ◽  
Intracellular Energy ◽  
G Protein Coupled ◽  
Extracellular Signalling

Adenosine 5′-triphosphate acts as an extracellular signalling molecule (purinergic signalling), as well as an intracellular energy source. Adenosine 5′-triphosphate receptors have been cloned and characterised. P1 receptors are selective for adenosine, a breakdown product of adenosine 5′-triphosphate after degradation by ectonucleotidases. Four subtypes are recognised, A1, A2A, A2B and A3 receptors. P2 receptors are activated by purine and by pyrimidine nucleotides. P2X receptors are ligand-gated ion channel receptors (seven subunits (P2X1-7)), which form trimers as both homomultimers and heteromultimers. P2Y receptors are G protein-coupled receptors (eight subtypes (P2Y1/2/4/6/11/12/13/14)). There is both purinergic short-term signalling and long-term (trophic) signalling. The cloning of P2X-like receptors in primitive invertebrates suggests that adenosine 5′-triphosphate is an early evolutionary extracellular signalling molecule. Selective purinoceptor agonists and antagonists with therapeutic potential have been developed for a wide range of diseases, including thrombosis and stroke, dry eye, atherosclerosis, kidney failure, osteoporosis, bladder incontinence, colitis, neurodegenerative diseases and cancer.

scholarly journals Geoffrey Burnstock. 10 May 1929—3 June 2020

2021 ◽  
Author(s):  
R. Alan North ◽  
Marcello Costa
Keyword(s):  
P2y Receptors ◽  
Autonomic Nerves ◽  
Purine Nucleotides ◽  
Biomedical Scientist ◽  
Signalling Molecule ◽  
University College London ◽  
University Colleges ◽  
The University ◽  
G Protein Coupled ◽  
Extracellular Signalling

Geoffrey Burnstock was a biomedical scientist who gained renown for his discovery that adenosine 5′-triphosphate (ATP) functions as an extracellular signalling molecule. Born in London and educated at King's and University colleges, he did postdoctoral work at Mill Hill and Oxford. He moved in 1959 to the Department of Zoology at the University of Melbourne because he sensed there a greater freedom to challenge established thinking in physiology. His group found that transmission from sympathetic and parasympathetic autonomic nerves to smooth muscle was in some places not mediated by the accepted chemical messengers (noradrenaline and acetylcholine). He amassed evidence that ATP was this non-adrenergic, non-cholinergic transmitter, using biochemical, histological and electrophysiological approaches: heretically, he styled this ‘purinergic transmission’. Geoff further upset dogma in the 1970s by proposing ‘co-transmission’ in which some nerves released ATP in addition to either noradrenaline or acetylcholine. He distinguished pharmacologically P1 receptors (activated best by adenosine and blocked by xanthines) and P2 receptors (activated best by purine nucleotides such as ATP) and he proposed in 1985 that the latter embraced P2X (ion channel) and P2Y (G protein-coupled) subtypes: about 10 years later these categories were substantiated by cDNA cloning. From 1975 until his retirement in 1997, Geoff was head of the Department of Anatomy and Embryology at University College London (UCL), which he developed energetically into a large and strong research department. Later, as head of the Autonomic Research Institute at the Royal Free (part of UCL), he continued to collaborate extensively, and founded several journals and international professional societies. He widely sought clinical benefit for his discoveries, and both P2X and P2Y receptors have been developed as the targets of useful therapeutics (gefapixant, clopidogrel). Geoff was proud of his modest, rather humble, background and eschewed formality. He may have smiled when his early discoveries were met with cynicism, even ridicule (‘pure-imagine’ transmission noted one amusing critic), but this just reinforced his resolve and encouraged his encyclopaedic oeuvre.

Therapeutic Potential of Agonists and Antagonists of A1, A2a, A2b and A3 Adenosine Receptors

2019 ◽  
Vol 25 (26) ◽  
pp. 2892-2905 ◽  
Author(s):  
Sumit Jamwal ◽  
Ashish Mittal ◽  
Puneet Kumar ◽  
Dana M. Alhayani ◽  
Amal Al-Aboudi
Keyword(s):  
Nervous System ◽  
Therapeutic Potential ◽  
The Body ◽  
Membrane Receptors ◽  
Physiological Importance ◽  
Physiological Processes ◽  
Central Nervous Systems ◽  
Energy Consuming ◽  
Metabolic Dysfunctions ◽  
G Protein Coupled

Adenosine is a naturally occurring nucleoside and an essential component of the energy production and utilization systems of the body. Adenosine is formed by the degradation of adenosine-triphosphate (ATP) during energy-consuming processes. Adenosine regulates numerous physiological processes through activation of four subtypes of G-protein coupled membrane receptors viz. A1, A2A, A2B and A3. Its physiological importance depends on the affinity of these receptors and the extracellular concentrations reached. ATP acts as a neurotransmitter in both peripheral and central nervous systems. In the peripheral nervous system, ATP is involved in chemical transmission in sensory and autonomic ganglia, whereas in central nervous system, ATP, released from synaptic terminals, induces fast excitatory postsynaptic currents. ATP provides the energetics for all muscle movements, heart beats, nerve signals and chemical reactions inside the body. Adenosine has been traditionally considered an inhibitor of neuronal activity and a regulator of cerebral blood flow. Since adenosine is neuroprotective against excitotoxic and metabolic dysfunctions observed in neurological and ocular diseases, the search for adenosinerelated drugs regulating adenosine transporters and receptors can be important for advancement of therapeutic strategies against these diseases. This review will summarize the therapeutic potential and recent SAR and pharmacology of adenosine and its receptor agonists and antagonists.

The Therapeutic Potential of Purinergic Receptors in Alzheimer’s Disease and Promising Therapeutic Modulators

2020 ◽  
Vol 20 ◽  
Author(s):  
Lili Pan ◽  
Yu Ma ◽  
Yunchun Li ◽  
Haoxing Wu ◽  
Rui Huang ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Purinergic Receptors ◽  
Therapeutic Potential ◽  
Purinergic Signaling ◽  
Memory Loss ◽  
Related Research ◽  
Central Nervous System Disorders ◽  
G Protein Coupled

Abstract:: Recent studies have proven that the purinergic signaling pathway plays a key role in neurotransmission and neuromodulation, and is involved in various neurodegenerative diseases and psychiatric disorders. With the characterization of the subtypes of receptors in purinergic signaling, i.e. the P1 (adenosine), P2X (ion channel) and P2Y (G protein-coupled), more attentions were paid to the pathophysiology and therapeutic potential of purinergic signaling in central nervous system disorders. Alzheimer’s disease (AD) is a progressive and deadly neurodegenerative disease that is characterized by memory loss, cognitive impairment and dementia. However, as drug development aimed to prevent or control AD follows a series of failures in recent years, more researchers focused on the neuroprotection-related mechanisms such as purinergic signaling in AD patients to find a potential cure. This article reviews the recent discoveries of purinergic signaling in AD, summaries the potential agents as modulators for the receptors of purinergic signaling in AD related research and treatments. Thus, our paper provided an insight for purinergic signaling in the development of anti-AD therapies.

Isoform-Selective PI3K Inhibitors for Various Diseases

2020 ◽  
Vol 20 (12) ◽  
pp. 1074-1092 ◽  
Author(s):  
Rammohan R.Y. Bheemanaboina
Keyword(s):  
Intracellular Signaling ◽  
Kinase Inhibitors ◽  
Therapeutic Potential ◽  
Type I ◽  
Selective Inhibitors ◽  
Pi3k Inhibitors ◽  
Wide Range ◽  
Lipid Kinases ◽  
Isoform Selectivity

Phosphoinositide 3-kinases (PI3Ks) are a family of ubiquitously distributed lipid kinases that control a wide variety of intracellular signaling pathways. Over the years, PI3K has emerged as an attractive target for the development of novel pharmaceuticals to treat cancer and various other diseases. In the last five years, four of the PI3K inhibitors viz. Idelalisib, Copanlisib, Duvelisib, and Alpelisib were approved by the FDA for the treatment of different types of cancer and several other PI3K inhibitors are currently under active clinical development. So far clinical candidates are non-selective kinase inhibitors with various off-target liabilities due to cross-reactivities. Hence, there is a need for the discovery of isoform-selective inhibitors with improved efficacy and fewer side-effects. The development of isoform-selective inhibitors is essential to reveal the unique functions of each isoform and its corresponding therapeutic potential. Although the clinical effect and relative benefit of pan and isoformselective inhibition will ultimately be determined, with the development of drug resistance and the demand for next-generation inhibitors, it will continue to be of great significance to understand the potential mechanism of isoform-selectivity. Because of the important role of type I PI3K family members in various pathophysiological processes, isoform-selective PI3K inhibitors may ultimately have considerable efficacy in a wide range of human diseases. This review summarizes the progress of isoformselective PI3K inhibitors in preclinical and early clinical studies for anticancer and other various diseases.

scholarly journals Emerging Molecular Receptors for the Specific-Target Delivery of Ruthenium and Gold Complexes into Cancer Cells

Molecules ◽  
2021 ◽  
Vol 26 (11) ◽  
pp. 3153
Author(s):  
João Franco Machado ◽  
João D. G. Correia ◽  
Tânia S. Morais
Keyword(s):  
Progesterone Receptors ◽  
Biological Evaluation ◽  
Cell Organelles ◽  
Gold Complexes ◽  
Main Research ◽  
Wide Range ◽  
Cancer Types ◽  
Organometallic Molecules ◽  
G Protein Coupled

Cisplatin and derivatives are highly effective in the treatment of a wide range of cancer types; however, these metallodrugs display low selectivity, leading to severe side effects. Additionally, their administration often results in the development of chemoresistance, which ultimately results in therapeutic failure. This scenario triggered the study of other transition metals with innovative pharmacological profiles as alternatives to platinum, ruthenium- (e.g., KP1339 and NAMI-A) and gold-based (e.g., Auranofin) complexes being among the most advanced in terms of clinical evaluation. Concerning the importance of improving the in vivo selectivity of metal complexes and the current relevance of ruthenium and gold metals, this review article aims to survey the main research efforts made in the past few years toward the design and biological evaluation of target-specific ruthenium and gold complexes. Herein, we give an overview of the inorganic and organometallic molecules conjugated to different biomolecules for targeting membrane proteins, namely cell adhesion molecules, G-protein coupled receptors, and growth factor receptors. Complexes that recognize the progesterone receptors or other targets involved in metabolic pathways such as glucose transporters are discussed as well. Finally, we describe some complexes aimed at recognizing cell organelles or compartments, mitochondria being the most explored. The few complexes addressing targeted gene therapy are also presented and discussed.

scholarly journals Bioactive potential of natural biomaterials: identification, retention and assessment of biological properties

2021 ◽  
Vol 6 (1) ◽  
Author(s):  
Kieran Joyce ◽  
Georgina Targa Fabra ◽  
Yagmur Bozkurt ◽  
Abhay Pandit
Keyword(s):  
Tissue Engineering ◽  
Therapeutic Potential ◽  
Biological Properties ◽  
Biological Assessment ◽  
Cross Linking ◽  
Natural Polymers ◽  
Drug Delivery Device ◽  
Biomedical Device ◽  
Wide Range ◽  
Bioactive Potential

AbstractBiomaterials have had an increasingly important role in recent decades, in biomedical device design and the development of tissue engineering solutions for cell delivery, drug delivery, device integration, tissue replacement, and more. There is an increasing trend in tissue engineering to use natural substrates, such as macromolecules native to plants and animals to improve the biocompatibility and biodegradability of delivered materials. At the same time, these materials have favourable mechanical properties and often considered to be biologically inert. More importantly, these macromolecules possess innate functions and properties due to their unique chemical composition and structure, which increase their bioactivity and therapeutic potential in a wide range of applications. While much focus has been on integrating these materials into these devices via a spectrum of cross-linking mechanisms, little attention is drawn to residual bioactivity that is often hampered during isolation, purification, and production processes. Herein, we discuss methods of initial material characterisation to determine innate bioactivity, means of material processing including cross-linking, decellularisation, and purification techniques and finally, a biological assessment of retained bioactivity of a final product. This review aims to address considerations for biomaterials design from natural polymers, through the optimisation and preservation of bioactive components that maximise the inherent bioactive potency of the substrate to promote tissue regeneration.

scholarly journals Mini-review: antibody therapeutics targeting G protein-coupled receptors and ion channels

2020 ◽  
Vol 3 (4) ◽  
pp. 257-264
Author(s):  
Catherine J Hutchings
Keyword(s):  
Ion Channels ◽  
Research And Development ◽  
Small Molecules ◽  
G Protein ◽  
Clinical Studies ◽  
G Protein Coupled Receptors ◽  
Protein Targets ◽  
Antibody Therapeutics ◽  
Wide Range ◽  
G Protein Coupled

Abstract Antibodies are now well established as therapeutics with many additional advantages over small molecules and peptides relative to their selectivity, bioavailability, half-life and effector function. Major classes of membrane-associated protein targets include G protein-coupled receptors (GPCRs) and ion channels that are linked to a wide range of disease indications across all therapeutic areas. This mini-review summarizes the antibody target landscape for both GPCRs and ion channels as well as current progress in the respective research and development pipelines with some example case studies highlighted from clinical studies, including those being evaluated for the treatment of symptoms in COVID-19 infection.

scholarly journals WIN55,212-2, a Dual Modulator of Cannabinoid Receptors and G Protein-Coupled Inward Rectifier Potassium Channels

Biomedicines ◽  
2021 ◽  
Vol 9 (5) ◽  
pp. 484
Author(s):  
Dongchen An ◽  
Steve Peigneur ◽  
Jan Tytgat
Keyword(s):  
Potassium Channels ◽  
Potassium Channel ◽  
G Protein ◽  
Cannabinoid Receptors ◽  
Inward Rectifier ◽  
Xenopus Laevis Oocyte ◽  
Inward Rectifier Potassium Channels ◽  
Wide Range ◽  
Cb2 Receptors ◽  
G Protein Coupled

The coupling of cannabinoid receptors, CB1 and CB2, to G protein-coupled inward rectifier potassium channels, GIRK1 and GIRK2, modulates neuronal excitability in the human brain. The present study established and validated the functional expression in a Xenopus laevis oocyte expression system of CB1 and CB2 receptors, interacting with heteromeric GIRK1/2 channels and a regulator of G protein signaling, RGS4. This ex vivo system enables the discovery of a wide range of ligands interacting orthosterically or allosterically with CB1 and/or CB2 receptors. WIN55,212-2, a non-selective agonist of CB1 and CB2, was used to explore the CB1- or CB2-GIRK1/2-RGS4 signaling cascade. We show that WIN55,212-2 activates CB1 and CB2 at low concentrations whereas at higher concentrations it exerts a direct block of GIRK1/2. This illustrates a dual modulatory function, a feature not described before, which helps to explain the adverse effects induced by WIN55,212-2 in vivo. When comparing the effects with other typical cannabinoids such as Δ9-THC, CBD, CP55,940, and rimonabant, only WIN55,212-2 can significantly block GIRK1/2. Interestingly, the inward rectifier potassium channel, IRK1, a non-G protein-coupled potassium channel important for setting the resting membrane voltage and highly similar to GIRK1 and GIRK2, is not sensitive to WIN55,212-2, Δ9-THC, CBD, CP55,940, or rimonabant. From this, it is concluded that WIN55,212-2 selectively blocks GIRK1/2.

scholarly journals The treatment effects of flaxseed-derived secoisolariciresinol diglycoside and its metabolite enterolactone on benign prostatic hyperplasia involve the G protein-coupled estrogen receptor 1

2016 ◽  
Vol 41 (12) ◽  
pp. 1303-1310 ◽  
Author(s):  
Guan-Yu Ren ◽  
Chun-Yang Chen ◽  
Wei-Guo Chen ◽  
Ya Huang ◽  
Li-Qiang Qin ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Estrogen Receptor ◽  
Benign Prostatic Hyperplasia ◽  
G Protein ◽  
Therapeutic Potential ◽  
Prostatic Hyperplasia ◽  
Docking Simulations ◽  
G Protein Coupled

Secoisolariciresinol diglucoside (SDG), a lignan extracted from flaxseed, has been shown to suppress benign prostatic hyperplasia (BPH). However, little is known about the mechanistic basis for its anti-BPH activity. The present study showed that enterolactone (ENL), the mammalian metabolite of SDG, shared the similar binding site of G1 on a new type of membranous estrogen receptor, G-protein-coupled estrogen eceptor 1 (GPER), by docking simulations method. ENL and G1 (the specific agonist of GPER) inhibited the proliferation of human prostate stromal cell line WPMY-1 as shown by MTT assay and arrested cell cycle at the G0/G1 phase, which was displayed by propidium iodide staining following flow cytometer examination. Silencing GPER by short interfering RNA attenuated the inhibitory effect of ENL on WPMY-1 cells. The therapeutic potential of SDG in the treatment of BPH was confirmed in a testosterone propionate-induced BPH rat model. SDG significantly reduced the enlargement of the rat prostate and the number of papillary projections of prostatic alveolus and thickness of the pseudostratified epithelial and stromal cells when comparing with the model group. Mechanistic studies showed that SDG and ENL increased the expression of GPER both in vitro and in vivo. Furthermore, ENL-induced cell cycle arrest may be mediated by the activation of GPER/ERK pathway and subsequent upregulation of p53 and p21 and downregulation of cyclin D1. This work, in tandem with previous studies, will enhance our knowledge regarding the mechanism(s) of dietary phytochemicals on BPH prevention and ultimately expand the scope of adopting alternative approaches in BPH treatment.

Antagonism of endogenous putative P2Y receptors reduces the growth of MDCK-derived cysts cultured in vitro

2007 ◽  
Vol 292 (1) ◽  
pp. F15-F25 ◽  
Author(s):  
Clare M. Turner ◽  
Brian F. King ◽  
Kaila S. Srai ◽  
Robert J. Unwin
Keyword(s):  
Therapeutic Potential ◽  
Cyst Formation ◽  
P2y Receptors ◽  
P2x Receptor ◽  
P2y Receptor ◽  
Cyst Size ◽  
Reactive Blue 2 ◽  
Cyst Growth

P2Y receptors couple to G proteins and either mobilize intracellular Ca2+ or alter cAMP levels to modulate the activity of Ca2+- and cAMP-sensitive ion channels. We hypothesize that increased ion transport into the lumen of MDCK cysts can osmotically drive fluid movement and increase cyst size. Furthermore, activation of the adenylate cyclase/cAMP pathway may trigger cell proliferation via an extracellular signal-related kinase cascade. To test this hypothesis, several P2Y receptor inhibitors were used on the MDCK in vitro model of renal cyst formation. The nonspecific P2 receptor inhibitors reactive blue 2 and suramin reduced cyst growth significantly, as did PPADS and, to a lesser extent, the P2Y1-specific antagonist MRS2179. Cyst growth was reduced by ∼50% when ATP was removed from the culture medium with apyrase, although stable analogs of ATP failed to increase cyst size. The nonselective P2X receptor inhibitor Coomassie brilliant blue G was ineffective at reducing cyst growth, suggesting no involvement of P2X receptors. Finally, the presence of selective inhibitors of ERK activation (either PD98059 or U0126) greatly reduced cyst growth, whereas in untreated cysts ERK activity was observed to increase with time. We conclude that stimulation of endogenous P2Y receptors by extracellular ATP increases growth of MDCK cysts via cAMP-dependent activation of the ERK pathway. P2Y receptor antagonists may have therapeutic potential in reducing cyst size and slowing disease progression; although further studies in vitro and in vivo are needed to investigate the specificity and role of these P2Y receptors in renal cystic diseases.

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