scholarly journals Mechanisms of ATP release in pain: role of pannexin and connexin channels

2021 ◽  
Author(s):  
Manuel F. Muñoz ◽  
Theanne N. Griffith ◽  
Jorge E. Contreras
Keyword(s):  
Purinergic Receptors ◽  
Pain Treatment ◽  
Purinergic Signaling ◽  
Atp Release ◽  
Current Evidence ◽  
Pain Processing ◽  
Potential Threat ◽  
Acute Response ◽  
Outstanding Question

AbstractPain is a physiological response to bodily damage and serves as a warning of potential threat. Pain can also transform from an acute response to noxious stimuli to a chronic condition with notable emotional and psychological components that requires treatment. Indeed, the management of chronic pain is currently an important unmet societal need. Several reports have implicated the release of the neurotransmitter adenosine triphosphate (ATP) and subsequent activation of purinergic receptors in distinct pain etiologies. Purinergic receptors are broadly expressed in peripheral neurons and the spinal cord; thus, purinergic signaling in sensory neurons or in spinal circuits may be critical for pain processing. Nevertheless, an outstanding question remains: what are the mechanisms of ATP release that initiate nociceptive signaling? Connexin and pannexin channels are established conduits of ATP release and have been suggested to play important roles in a variety of pathologies, including several models of pain. As such, these large-pore channels represent a new and exciting putative pharmacological target for pain treatment. Herein, we will review the current evidence for a role of connexin and pannexin channels in ATP release during nociceptive signaling, such as neuropathic and inflammatory pain. Collectively, these studies provide compelling evidence for an important role of connexins and pannexins in pain processing.

scholarly journals Pannexin-1 mediated ATP release in adipocytes is sensitive to glucose and insulin and modulates lipolysis and macrophage migration

2018 ◽  
Author(s):  
Marco Tozzi ◽  
Jacob B. Hansen ◽  
Ivana Novak
Keyword(s):  
Adipose Tissue ◽  
Purinergic Receptors ◽  
Purinergic Signaling ◽  
Cell Metabolism ◽  
Atp Release ◽  
Extracellular Atp ◽  
Adrenergic Stimulation ◽  
Pannexin 1 ◽  
White Adipocytes ◽  
Obesity And Diabetes

One-sentence summaryInsulin inhibits ATP release in adipocytesAbstractExtracellular ATP signaling is involved in many physiological and pathophysiological processes, and purinergic receptors are targets for drug therapy in several diseases, including obesity and diabetes. Adipose tissue has crucial functions in lipid and glucose metabolism and adipocytes express purinergic receptors. However, the sources of extracellular ATP in adipose tissue are not yet characterized.Here, we show that upon adrenergic stimulation white adipocytes release ATP through the pannexin-1 pore that is regulated by a cAMP-PKA dependent pathway. The ATP release correlates with increased cell metabolism, and extracellular ATP induces Ca2+ signaling and lipolysis in adipocytes and promotes macrophages migration. Most importantly, ATP release is markedly inhibited by insulin, and thereby auto/paracrine purinergic signaling in adipose tissue would be attenuated. Furthermore, we define the signaling pathway for insulin regulated ATP release.Our findings reveal the insulin-pannexin-1-purinergic signaling cross-talk in adipose tissue and we propose that deregulation of this signaling may underlie adipose tissue inflammation and type-2 diabetes.

scholarly journals Purinergic Signaling Mediates PTH and Fluid Flow-Induced Osteoblast Proliferation

2021 ◽  
Vol 2021 ◽  
pp. 1-8
Author(s):  
Yanghui Xing ◽  
Liang Song ◽  
Yingying Zhang ◽  
Tengyu Zhang ◽  
Jian Li ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Fluid Flow ◽  
Mechanical Stimulation ◽  
Purinergic Receptors ◽  
Bone Growth ◽  
Purinergic Signaling ◽  
Atp Release ◽  
Osteoblast Proliferation ◽  
Creb Phosphorylation ◽  
Mechanical Signals

Both parathyroid hormone (PTH) and mechanical signals are able to regulate bone growth and regeneration. They also can work synergistically to regulate osteoblast proliferation, but little is known about the mechanisms how PTH and mechanical signals interact with each other during this process. In this study, we investigated responses of MC3T3-E1 osteoblasts to PTH and oscillatory fluid flow. We found that osteoblasts are more sensitive to mechanical signals in the presence of PTH according to ERK1/2 phosphorylation, ATP release, CREB phosphorylation, and cell proliferation. PTH may also reduce the osteoblast refractory period after desensitization due to mechanical signals. We further found that the synergistic responses of osteoblasts to fluid flow or ATP with PTH had similar patterns, suggesting that synergy between fluid flow and PTH may be through the ATP pathway. After we inhibited ATP effects using apyrase in osteoblasts, their synergistic responses to mechanical stimulation and PTH were also inhibited. Additionally, knocking down P2Y2 purinergic receptors can significantly attenuate osteoblast synergistic responses to mechanical stimulation and PTH in terms of ERK1/2 phosphorylation, CREB phosphorylation, and cell proliferation. Thus, our results suggest that PTH enhances mechanosensitivity of osteoblasts via a mechanism involving ATP and P2Y2 purinergic receptors.

Evidences of G-Coupled Protein Receptor (GPCR) signaling in the human malaria parasite Plasmodium falciparum for sensing its microenvironment and the role of purinergic signaling in malaria parasites..

2020 ◽  
Vol 20 ◽  
Author(s):  
Pedro H. S. Pereira ◽  
Lucas Borges-Pereira ◽  
Célia R. S. Garcia
Keyword(s):  
Purinergic Receptors ◽  
Purinergic Signaling ◽  
Electrical Stimulus ◽  
Early 19Th Century ◽  
Protein Receptor ◽  
Parasite Plasmodium ◽  
Parasite Plasmodium Falciparum ◽  
Initial Resistance ◽  
G Protein Coupled

: The nucleotides were discovered in the early 19th century and a few years later the role of such molecules in the energy metabolism and cell survival was postulated. In 1972 a pioneer work by Burnstock and colleagues suggested that ATP could work also a neurotransmitter, which was known as the “purinergic hypothesis”. The idea of ATP working as signaling molecule faced initial resistance until the discovery of the receptors for ATP and other nucleotides, being called purinergic receptors. Among the purinergic receptors, the P2Y family is of great importance because it comprises G protein-coupled receptors (GPCRs). GPCRs are widespread among different organisms. These receptors work in the cells' ability to sense the external environment which involves: to sense a dangerous situation or detect a pheromone through smell; the taste of food that should not be eaten; respond to hormones that alter metabolism according to the body's need; or even transform light into an electrical stimulus to generate vision. Advances in understanding the mechanism of action of GPCRs shed light on increasingly promising treatments for diseases that have hitherto remained incurable, or the possibility of abolishing side effects from therapies widely used today.

scholarly journals The Role of Purinergic Receptors in the Circadian System

2020 ◽  
Vol 21 (10) ◽  
pp. 3423
Author(s):  
Amira A.H. Ali ◽  
Gayaneh Avanes Avakian ◽  
Charlotte Von Gall
Keyword(s):  
Purinergic Receptors ◽  
Purinergic Signaling ◽  
Circadian System ◽  
Internal Time ◽  
Peripheral Oscillators ◽  
Pathological Conditions ◽  
Environmental Light ◽  
Extracellular Purines ◽  
Purines And Pyrimidines

The circadian system is an internal time-keeping system that synchronizes the behavior and physiology of an organism to the 24 h solar day. The master circadian clock, the suprachiasmatic nucleus (SCN), resides in the hypothalamus. It receives information about the environmental light/dark conditions through the eyes and orchestrates peripheral oscillators. Purinergic signaling is mediated by extracellular purines and pyrimidines that bind to purinergic receptors and regulate multiple body functions. In this review, we highlight the interaction between the circadian system and purinergic signaling to provide a better understanding of rhythmic body functions under physiological and pathological conditions.

scholarly journals Role of neuraxial drug delivery in cancer pain therapy

2020 ◽  
Vol 2 (4) ◽  
pp. FDD49
Author(s):  
Edgar Ross ◽  
Roshni Ramachandran ◽  
Jason D Ross ◽  
Ashish Bhandari ◽  
Patrick W Mantyh ◽  
...  
Keyword(s):  
Cancer Pain ◽  
Pain Treatment ◽  
Current Evidence ◽  
Oncologic Surgery ◽  
Cancer Pain Therapy ◽  
Continued Use ◽  
Long Term Prognosis ◽  
New Treatment

Opioids have long been the mainstay of cancer pain treatment and have been used without any consideration for their effect on cancer growth and long-term prognosis. There is now growing evidence that the continued use of opioids for this indication should be reviewed and even reconsidered. Although current evidence and literature covering this subject is mixed and does not yet allow for a clear determination to be made about safety, there is enough data to support the search for new treatment paradigms, beginning with anesthesia for oncologic surgery and management of cancer pain over the disease course.

scholarly journals Evidence for Gd3+ inhibition of membrane ATP permeability and purinergic signaling

1999 ◽  
Vol 277 (6) ◽  
pp. G1222-G1230 ◽  
Author(s):  
Richard M. Roman ◽  
Andrew P. Feranchak ◽  
Amy K. Davison ◽  
Erik M. Schwiebert ◽  
J. Gregory Fitz
Keyword(s):  
Cell Volume ◽  
Purinergic Signaling ◽  
Atp Release ◽  
Physiological Role ◽  
Rat Hepatocytes ◽  
Extracellular Atp ◽  
Inhibitory Effects ◽  
Cellular Mechanisms ◽  
Volume Recovery

Extracellular ATP functions as an important autocrine and paracrine signal that modulates a broad range of cell and organ functions through activation of purinergic receptors in the plasma membrane. Because little is known of the cellular mechanisms involved in ATP release, the purpose of these studies was to evaluate the potential role of the lanthanide Gd3+ as an inhibitor of ATP permeability and to assess the physiological implications of impaired purinergic signaling in liver cells. In rat hepatocytes and HTC hepatoma cells, increases in cell volume stimulate ATP release, and the localized increase in extracellular ATP increases membrane Cl− permeability and stimulates cell volume recovery through activation of P2 receptors. In cells in culture, spontaneous ATP release, as measured by a luciferin-luciferase-based assay, was always detectable under control conditions, and extracellular ATP concentrations increased 2- to 14-fold after increases in cell volume. Gd3+(200 μM) inhibited volume-sensitive ATP release by >90% ( P < 0.001), inhibited cell volume recovery from swelling ( P < 0.01), and uncoupled cell volume from increases in membrane Cl− permeability ( P < 0.01). Moreover, Gd3+ had similar inhibitory effects on ATP release from other liver and epithelial cell models. Together, these findings support an important physiological role for constitutive release of ATP as a signal coordinating cell volume and membrane ion permeability and suggest that Gd3+ might prove to be an effective inhibitor of ATP-permeable channels once they are identified.

scholarly journals Mitochondria regulate TRPV4 mediated release of ATP

2021 ◽  
Author(s):  
Xun Zhang ◽  
Matthew Lee ◽  
Charlotte Buckley ◽  
Calum Wilson ◽  
John McCarron
Keyword(s):  
Purinergic Receptors ◽  
Experimental Approach ◽  
Channel Blocker ◽  
Atp Release ◽  
Cyclopiazonic Acid ◽  
Inositol Triphosphate ◽  
Resistance Arteries ◽  
Synthase Inhibitor ◽  
Trpv4 Channel

Background and Purpose Ca influx via TRPV4 triggers Ca release from the IP-sensitive internal store to generate repetitive oscillations. While mitochondria are acknowledged regulators of IP-mediated Ca release, how TRPV4-mediated Ca signals are regulated by mitochondria is unknown. We show that depolarised mitochondria switch TRPV4 signalling from relying on Ca-induced Ca release at IP receptors, to being independent of Ca influx and instead mediated by ATP release via pannexins. Experimental Approach TRPV4 evoked Ca signals were individually examined in hundreds of cells in the endothelium of rat mesenteric resistance arteries using the indicator Cal520. Key ResultsTRPV4 activation with GSK1016790A(GSK) generated repetitive Ca oscillations that required Ca influx. However, when the mitochondrial membrane potential was depolarised, by the uncoupler CCCP or complex I inhibitor rotenone, TRPV4 activation generated large propagating, multicellular, Ca waves in the absence of external Ca. The ATP synthase inhibitor oligomycin did not potentiate TRPV4 mediated Ca signals. GSK-evoked Ca waves, when mitochondria were depolarised, were blocked by the TRPV4 channel blocker HC067047, the SERCA inhibitor cyclopiazonic acid, the phospholipase C (PLC) blocker U73122 and the inositol triphosphate receptor (IP R) blocker caffeine. The Ca waves were also inhibited by the extracellular ATP blockers suramin and apyrase and the pannexin blocker probenecid. Conclusion and Implications These results highlight a previously unknown role of mitochondria in shaping TRPV4 mediated Ca signalling by facilitating ATP release. When mitochondria are depolarised, TRPV4-mediated release of ATP via pannexin channels activates plasma membrane purinergic receptors to trigger IP evoked Ca release.

scholarly journals Purinergic regulation: From a risky hypothesis to a triumphant theory

2021 ◽  
Vol 16 (3) ◽  
pp. 190-202
Author(s):  
Mohammad Kamran Sarkandi ◽  
◽  
Natalia Serebryanaya ◽  
◽  
Keyword(s):  
Functional State ◽  
Purinergic Receptors ◽  
Purinergic Signaling ◽  
Signal Transmission ◽  
The Body ◽  
Extracellular Nucleotides ◽  
Receptor Interaction ◽  
First Time

With the discovery of the ATP structure in 1929, significant progress was made in understanding the role of nucleosides and nucleotides in the body. One of the most important breakthroughs is associated with the determination of the function of an autacoid in ATP, a participant in purinergic signal transmission. For the first time, this function of ATP was pointed out by Professor Geoffrey Burnstock in 1972. Purinergic signaling activators are extracellular nucleotides including ATP, ADP, UTP, UDP, and adenosine nucleoside. The purinergic signaling pathway begins with the synthesis and intracellular accumulation of nucleotides, and then their release from the cell under various physiological and pathological conditions. In the extracellular spaces, nucleotides are hydrolyzed by various enzymes with the removal of phosphate groups, which leads to the appearance of various regulatory molecules that interact with P1 and P2 purinergic receptors. This ligand-receptor interaction changes the functional state of the target cell. In turn, the expression of purinergic receptors changes depending on the functional state of the cell. The participation of purinergic regulation in the development of many diseases indicates that by changing the concentration of signaling molecules, it is possible to change the course of pathological processes, in particular the activity of inflammation and the direction of immune responses. This article provides a brief review of the literature on the structure of nucleotide and nucleoside autacoids, enzymes involved in their metabolism, specific purinergic receptors.

Expression and contribution of satellite glial cells purinoceptors to pain transmission in sensory ganglia: an update

2010 ◽  
Vol 6 (1) ◽  
pp. 31-42 ◽  
Author(s):  
Giovanni Villa ◽  
Marta Fumagalli ◽  
Claudia Verderio ◽  
Maria P. Abbracchio ◽  
Stefania Ceruti
Keyword(s):  
Glial Cells ◽  
Pain Treatment ◽  
Purinergic Signaling ◽  
Original Data ◽  
P2y Receptors ◽  
Receptor Expression ◽  
Sensory Ganglia ◽  
Satellite Glial Cells ◽  
Pain Transmission

The role of adenosine-5′-triphosphate (ATP) and of the ligand-gated P2X3receptor in neuronal dorsal root ganglia (DRG) pain transmission is relatively well established. Much less is known about the purinergic system in trigeminal ganglia (TG), which are involved in certain types of untreatable neuropathic and inflammatory pain, as well as in migraine. Emerging data suggest that purinergic metabotropic P2Y receptors on both neurons and satellite glial cells (SGCs) may also participate in both physiological and pathological pain development. Here, we provide an updated literature review on the role of purinergic signaling in sensory ganglia, with special emphasis on P2Y receptors on SGCs. We also provide new original data showing a time-dependent downregulation of P2Y2and P2Y4receptor expression and function in purified SGCs cultures from TG, in comparison with primary mixed neuron–SGCs cultures. These data highlight the importance of the neuron–glia cross-talk in determining the SGCs phenotype. Finally, we show that, in mixed TG cultures, both adenine and guanosine induce intracellular calcium transients in neurons but not in SGCs, suggesting that also these purinergic-related molecules can participate in pain signaling. These findings may have relevant implications for the development of new therapeutic strategies for chronic pain treatment.

Collagen-Induced Platelet Aggregation: -Evidence Against the Essential Role of Platelet Adenosine Diphosphate

1979 ◽  
Vol 42 (04) ◽  
pp. 1193-1206 ◽  
Author(s):  
Barbara Nunn
Keyword(s):  
Platelet Aggregation ◽  
Time Course ◽  
Essential Role ◽  
Atp Release ◽  
Adenosine Diphosphate ◽  
Human Platelets ◽  
High Doses ◽  
Induced Aggregation

SummaryThe hypothesis that platelet ADP is responsible for collagen-induced aggregation has been re-examined. It was found that the concentration of ADP obtaining in human PRP at the onset of aggregation was not sufficient to account for that aggregation. Furthermore, the time-course of collagen-induced release in human PRP was the same as that in sheep PRP where ADP does not cause release. These findings are not consistent with claims that ADP alone perpetuates a collagen-initiated release-aggregation-release sequence. The effects of high doses of collagen, which released 4-5 μM ADP, were not inhibited by 500 pM adenosine, a concentration that greatly reduced the effect of 300 μM ADP. Collagen caused aggregation in ADP-refractory PRP and in platelet suspensions unresponsive to 1 mM ADP. Thus human platelets can aggregate in response to collagen under circumstances in which they cannot respond to ADP. Apyrase inhibited aggregation and ATP release in platelet suspensions but not in human PRP. Evidence is presented that the means currently used to examine the role of ADP in aggregation require investigation.

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