scholarly journals ATP and the purine type 2 X7 receptor affect sleep

2010 ◽  
Vol 109 (5) ◽  
pp. 1318-1327 ◽  
Author(s):  
James M. Krueger ◽  
Ping Taishi ◽  
Alok De ◽  
Christopher J. Davis ◽  
Bradley D. Winters ◽  
...  
Keyword(s):  
Sleep Deprivation ◽  
Somatosensory Cortex ◽  
Interleukin 1 ◽  
Time Of Day ◽  
Extracellular Atp ◽  
P2 Receptors ◽  
Receptor Protein ◽  
P2 Receptor ◽  
Delta Power

Sleep is dependent upon prior brain activities, e.g., after prolonged wakefulness sleep rebound occurs. These effects are mediated, in part, by humoral sleep regulatory substances such as cytokines. However, the property of wakefulness activity that initiates production and release of such substances and thereby provides a signal for indexing prior waking activity is unknown. We propose that extracellular ATP, released during neuro- and gliotransmission and acting via purine type 2 (P2) receptors, is such a signal. ATP induces cytokine release from glia. Cytokines in turn affect sleep. We show here that a P2 receptor agonist, 2′(3′)- O-(4-benzoylbenzoyl)adenosine 5′-triphosphate (BzATP), increased non-rapid eye movement sleep (NREMS) and electroencephalographic (EEG) delta power while two different P2 receptor antagonists, acting by different inhibitory mechanisms, reduced spontaneous NREMS in rats. Rat P2X7 receptor protein varied in the somatosensory cortex with time of day, and P2X7 mRNA was altered by interleukin-1 treatment, by sleep deprivation, and with time of day in the hypothalamus and somatosensory cortex. Mice lacking functional P2X7 receptors had attenuated NREMS and EEG delta power responses to sleep deprivation but not to interleukin-1 treatment compared with wild-type mice. Data are consistent with the hypothesis that extracellular ATP, released as a consequence of cell activity and acting via P2 receptors to release cytokines and other sleep regulatory substances, provides a mechanism by which the brain could monitor prior activity and translate it into sleep.

scholarly journals Extracellular ATP Mediates Cancer Cell Migration and Invasion Through Increased Expression of Cyclooxygenase 2

2021 ◽  
Vol 11 ◽  
Author(s):  
Shilpa Sharma ◽  
Harshit Kalra ◽  
Ravi Shankar Akundi
Keyword(s):  
Cell Migration ◽  
Tumor Microenvironment ◽  
Extracellular Atp ◽  
P2 Receptors ◽  
Cyclooxygenase 2 ◽  
Migration And Invasion ◽  
P2 Receptor ◽  
Cell Migration And Invasion ◽  
Cox 2 ◽  
Mcf 7

The tumor microenvironment plays a major role in the ability of the tumor cells to undergo metastasis. A major player of tumors gaining metastatic property is the inflammatory protein, cyclooxygenase 2 (COX-2). Several tumors show upregulation of this protein, which has been implicated in mediating metastasis in various cancer types such as of colon, breast and lung. In this report, we show that the concentration of extracellular ATP (eATP) is increased in response to cell death mediated by chemotherapeutic agents such as doxorubicin. By using three different cell-lines—HeLa (cervical), IMR-32 (neuronal) and MCF-7 (breast)—we show that this eATP goes on to act on purinergic (P2) receptors. Among the various P2 receptors expressed in these cells we identified P2X7, in IMR-32 and MCF-7 cells, and P2Y12, in HeLa cells, as important in modulating cell migration and invasion. Downstream of the P2 receptor activation, both p42/44 mitogen-activated protein kinase (MAPK) and the p38 MAPK are activated in these cells. These result in an increase in the expression of COX-2 mRNA and protein. We also observe an increase in the activity of matrix metalloproteinase 2 (MMP-2) enzyme in these cells. Blocking the P2 receptors not only blocks migration and invasion, but also COX-2 synthesis and MMP-2 activity. Our results show the link between purinergic receptors and COX-2 expression. Increased levels of ATP in the tumor microenvironment, therefore, leads to increased COX-2 expression, which, in turn, affords migratory and invasive properties to the tumor. This provides P2 receptor-based anti-inflammatory drugs (PBAIDs) a potential opportunity to be explored as cancer therapeutics.

scholarly journals Extracellular ATP-induced calcium signaling in mIMCD-3 cells requires both P2X and P2Y purinoceptors

2004 ◽  
Vol 287 (2) ◽  
pp. F204-F214 ◽  
Author(s):  
Shen-Ling Xia ◽  
Lanjun Wang ◽  
Melanie N. Cash ◽  
Xueling Teng ◽  
Ruth A. Schwalbe ◽  
...  
Keyword(s):  
Collecting Duct ◽  
Duct Cell ◽  
P2y Receptors ◽  
Extracellular Atp ◽  
P2 Receptors ◽  
Channel Blockers ◽  
P2 Receptor ◽  
Bath Solution ◽  
Intracellular Ca ◽  
Sustained Increase

Kidney tubules are targets for the activation of locally released nucleotides through multiple P2 receptor types. Activation of these P2 receptors modulates cellular Ca2+signaling and downstream cellular function. The purpose of this study was to determine whether P2 receptors were present in mIMCD-3 cells, a mouse inner medullary collecting duct cell line, and if so, to examine their link with intracellular Ca2+homeostasis. To monitor intracellular Ca2+concentration ([Ca2+]i), experiments were conducted using the fluorescent dye fura 2. ATP (0.1–100 μM) produced a dose-dependent increase in [Ca2+]iin a physiological Ca2+-containing solution, with an EC50of 2.5 μM. The P2-receptor antagonist PPADS reduced the effect of ATP on [Ca2+]i, and the P1-receptor agonist adenosine caused only a small increase in [Ca2+]i. Preincubation of cells with the phospholipase C antagonist U-73122 blocked the ATP-induced increase in [Ca2+]i, indicating P2Y receptors were involved in this process. In a Ca2+-free bath solution, thapsigargin and ATP induced intracellular Ca2+release from an identical pool. Nucleotides caused an increase in [Ca2+]iin the potency order of UTP = ATP > ATPγS > ADP > UDP that is best fitted with the P2Y2subtype profile. Although the P2Y agonist UTP induced a similar large transient increase in [Ca2+]ias did ATP, a small but sustained increase in [Ca2+]ioccurred only in ATP-stimulated cells, suggesting the role of P2X receptors in Ca2+influx. The sustained increase in [Ca2+]icould be blocked by either nonselective cation channel blockers Gd3+or P2X antagonists PPADS and PPNDS. Furthermore, when either Gd3+or PPNDS was applied to the bath solution before ATP application, the ATP-induced increase in [Ca2+]iwas significantly reduced. Both RT-PCR and Western blotting corroborated the presence of P2X1and P2Y2receptors. These studies demonstrate that mIMCD-3 cells have both P2X and P2Y subtype receptors and that the activation of both P2X and P2Y receptors by extracellular ATP appears to be required to regulate intracellular Ca2+signaling.

scholarly journals Metformin reduces NAD(P)H oxidase activity in mouse cultured podocytes through purinergic dependent mechanism by increasing extracellular ATP concentration.

1970 ◽  
Vol 60 (4) ◽  
Author(s):  
Agnieszka Piwkowska ◽  
Dorota Rogacka ◽  
Maciej Jankowski ◽  
Stefan Angielski
Keyword(s):  
Oxidase Activity ◽  
Extracellular Atp ◽  
P2 Receptors ◽  
Diabetic Patients ◽  
Ampk Phosphorylation ◽  
Atp Concentration ◽  
Hypoglycemic Drug ◽  
Ampk Activity ◽  
Radical Generation

Hyperglycemia affects the functioning numbers of podocytes and leads to a gradual decline of renal function. The normalization of glucose level is a principle therapeutic goal in diabetic patients and metformin is a popular hypoglycemic drug used in type 2 diabetes mellitus. Metformin activates AMP-activated kinase (AMPK) and decreases NAD(P)H oxidase activity in podocytes leading to reduction of free radical generation. Similar effects are observed after activation of P2 receptors. Therefore, we investigated whether metformin increases extracellular ATP concentration and affects the activities of NAD(P)H oxidase and AMPK through P2 receptors. Experiments were performed on cultured mouse podocytes. NAD(P)H oxidase activity was measured by chemiluminescence and changes in AMPK activity were estimated by immunoblotting against AMPKα-Thr(172)-P. Metformin increased extracellular ATP concentration by reduction of ecto-ATPase activity, decreased NAD(P)H oxidase activity and increased AMPK phosphorylation. A P2 receptor antagonist, suramin (300 µM), prevented metformin action on NAD(P)H oxidase and AMPK phosphorylation. The data suggests a novel mechanism of metformin action, at least in podocytes. Metformin, which increases extracellular ATP concentration leads to activation of P2 receptors and consequent modulation of the podocytes' metabolism through AMPK and NAD(P)H oxidase which, in turn, may affect podocyte functioning.

scholarly journals Time-of-Day-Dependent Effects of Bromocriptine to Ameliorate Vascular Pathology and Metabolic Syndrome in SHR Rats Held on High Fat Diet

2021 ◽  
Vol 22 (11) ◽  
pp. 6142
Author(s):  
Michael Ezrokhi ◽  
Yahong Zhang ◽  
Shuqin Luo ◽  
Anthony H. Cincotta
Keyword(s):  
Type 2 Diabetes ◽  
Metabolic Syndrome ◽  
High Fat Diet ◽  
Nitrosative Stress ◽  
Time Of Day ◽  
Vascular Pathology ◽  
Mrna Levels ◽  
High Fat ◽  
Nadph Oxidase 4

The treatment of type 2 diabetes patients with bromocriptine-QR, a unique, quick release micronized formulation of bromocriptine, improves glycemic control and reduces adverse cardiovascular events. While the improvement of glycemic control is largely the result of improved postprandial hepatic glucose metabolism and insulin action, the mechanisms underlying the drug’s cardioprotective effects are less well defined. Bromocriptine is a sympatholytic dopamine agonist and reduces the elevated sympathetic tone, characteristic of metabolic syndrome and type 2 diabetes, which potentiates elevations of vascular oxidative/nitrosative stress, known to precipitate cardiovascular disease. Therefore, this study investigated the impact of bromocriptine treatment upon biomarkers of vascular oxidative/nitrosative stress (including the pro-oxidative/nitrosative stress enzymes of NADPH oxidase 4, inducible nitric oxide (iNOS), uncoupled endothelial nitric oxide synthase (eNOS), the pro-inflammatory/pro-oxidative marker GTP cyclohydrolase 1 (GTPCH 1), and the pro-vascular health enzyme, soluble guanylate cyclase (sGC) as well as the plasma level of thiobarbituric acid reactive substances (TBARS), a circulating marker of systemic oxidative stress), in hypertensive SHR rats held on a high fat diet to induce metabolic syndrome. Inasmuch as the central nervous system (CNS) dopaminergic activities both regulate and are regulated by CNS circadian pacemaker circuitry, this study also investigated the time-of-day-dependent effects of bromocriptine treatment (10 mg/kg/day at either 13 or 19 h after the onset of light (at the natural waking time or late during the activity period, respectively) among animals held on 14 h daily photoperiods for 16 days upon such vascular biomarkers of vascular redox state, several metabolic syndrome parameters, and mediobasal hypothalamic (MBH) mRNA expression levels of neuropeptides neuropeptide Y (NPY) and agouti-related protein (AgRP) which regulate the peripheral fuel metabolism and of mRNA expression of other MBH glial and neuronal cell genes that support such metabolism regulating neurons in this model system. Such bromocriptine treatment at ZT 13 improved (reduced) biomarkers of vascular oxidative/nitrosative stress including plasma TBARS level, aortic NADPH oxidase 4, iNOS and GTPCH 1 levels, and improved other markers of coupled eNOS function, including increased sGC protein level, relative to controls. However, bromocriptine treatment at ZT 19 produced no improvement in either coupled eNOS function or sGC protein level. Moreover, such ZT 13 bromocriptine treatment reduced several metabolic syndrome parameters including fasting insulin and leptin levels, as well as elevated systolic and diastolic blood pressure, insulin resistance, body fat store levels and liver fat content, however, such effects of ZT 19 bromocriptine treatment were largely absent versus control. Finally, ZT 13 bromocriptine treatment reduced MBH NPY and AgRP mRNA levels and mRNA levels of several MBH glial cell/neuronal genes that code for neuronal support/plasticity proteins (suggesting a shift in neuronal structure/function to a new metabolic control state) while ZT 19 treatment reduced only AgRP, not NPY, and was with very little effect on such MBH glial cell genes expression. These findings indicate that circadian-timed bromocriptine administration at the natural circadian peak of CNS dopaminergic activity (that is diminished in insulin resistant states), but not outside this daily time window when such CNS dopaminergic activity is naturally low, produces widespread improvements in biomarkers of vascular oxidative stress that are associated with the amelioration of metabolic syndrome and reductions in MBH neuropeptides and gene expressions known to facilitate metabolic syndrome. These results of such circadian-timed bromocriptine treatment upon vascular pathology provide potential mechanisms for the observed marked reductions in adverse cardiovascular events with circadian-timed bromocriptine-QR therapy (similarly timed to the onset of daily waking as in this study) of type 2 diabetes subjects and warrant further investigations into related mechanisms and the potential application of such intervention to prediabetes and metabolic syndrome patients as well.

Effect of interleukin-1 beta on EEG power density during sleep depends on circadian phase

1996 ◽  
Vol 270 (4) ◽  
pp. R830-R837 ◽  
Author(s):  
M. Lancel ◽  
S. Mathias ◽  
J. Faulhaber ◽  
T. Schiffelholz
Keyword(s):  
Power Density ◽  
Interleukin 1 ◽  
Time Of Day ◽  
Controlled Study ◽  
Randomized Experiments ◽  
Eeg Activity ◽  
Circadian Phase ◽  
Activity Phase ◽  
Eeg Power ◽  
A Minor

The cytokine interleukin (IL)-1 is a key mediator of the somnogenic response to immune challenge. In this vehicle-controlled study we evaluated circadian interference with the sleep-promoting effects of IL-1 beta. In two randomized experiments, rats were injected intracerebroventricularly with 5 ng IL-1 beta either at the beginning of the rest phase or at the beginning of the activity phase. Recordings were made during the 24 h preceding the injections (baseline) and during the first 12 postinjection hours. To avoid masking effects of light, the rats were maintained under a skeleton photoperiod during recording. During both the rest and activity phase, IL-1 beta induced fever and initially promoted non-rapid eye movement sleep (REMS). The effect of IL-1 beta on the duration of non-REMS and electroencephalogram (EEG) power densities within non-REMS was related to circadian phase. During the rest phase, IL-1 beta resulted in a minor increase in non-REMS duration but a prominent enhancement in EEG activity in the delta (0.5-4 Hz) and most other frequency bands. During the activity phase, IL-1 beta evoked a larger increase in the duration of non-REMS but hardly affected EEG activity within this state. Thus the effects of IL-1 beta on non-REMS are strongly influenced by diurnal phase. The alterations in EEG power density are in contrast to those elicited by sleep deprivation, which are largely independent of time of day. It is concluded that IL-1 beta activates EEG regulatory mechanisms mediated by processes that depend on circadian phase.

Assessing vigilance through a brief pencil and paper letter cancellation task (LCT): effects of one night of sleep deprivation and of the time of day

Ergonomics ◽  
1997 ◽  
Vol 40 (6) ◽  
pp. 613-630 ◽  
Author(s):  
MARIA CASAGRANDE ◽  
CRISTIANO VIOLANI ◽  
GIUSEPPE CURCIO ◽  
MARIO BERTINI
Keyword(s):  
Sleep Deprivation ◽  
Time Of Day ◽  
Cancellation Task ◽  
Pencil And Paper

scholarly journals Effect of P2 receptor blockade on cutaneous vasodilation during rest and exercise in the heat in young men

2018 ◽  
Vol 43 (3) ◽  
pp. 312-315
Author(s):  
Naoto Fujii ◽  
Robert D. Meade ◽  
Jeffrey C. Louie ◽  
Pegah Akbari ◽  
Pierre Boulay ◽  
...  
Keyword(s):  
Heat Exposure ◽  
P2 Receptors ◽  
Moderate Intensity ◽  
Receptor Blockade ◽  
P2 Receptor ◽  
Moderate Intensity Exercise ◽  
Cutaneous Vasodilation ◽  
Oxide Synthase ◽  
Rest And Exercise

We assessed the role of purinergic P2 receptors in the regulation of cutaneous vasodilation in young adults at rest and during intermittent moderate-intensity exercise in the heat (35 °C). P2 receptor blockade augmented resting cutaneous vasodilation but had no influence during and following exercise. This increase was partly diminished by nitric oxide synthase inhibition. These results suggest a functional role of P2 receptors in the regulation of cutaneous vascular tone during ambient heat exposure at rest.

scholarly journals A new function for ATP: activating cardiac sympathetic afferents during myocardial ischemia

2010 ◽  
Vol 299 (6) ◽  
pp. H1762-H1771 ◽  
Author(s):  
Liang-Wu Fu ◽  
John C. Longhurst
Keyword(s):  
Myocardial Ischemia ◽  
Cardiovascular Responses ◽  
P2 Receptors ◽  
Nerve Fibers ◽  
Disulfonic Acid ◽  
Dependent Manner ◽  
P2 Receptor ◽  
C Fibers ◽  
Spinal Afferents ◽  
Cardiac Afferents

Myocardial ischemia activates cardiac sympathetic afferents leading to chest pain and reflex cardiovascular responses. Brief myocardial ischemia leads to ATP release in the interstitial space. Furthermore, exogenous ATP and α,β-methylene ATP (α,β-meATP), a P2X receptor agonist, stimulate cutaneous group III and IV sensory nerve fibers. The present study tested the hypothesis that endogenous ATP excites cardiac afferents during ischemia through activation of P2 receptors. Nerve activity of single unit cardiac sympathetic afferents was recorded from the left sympathetic chain or rami communicates (T2-T5) in anesthetized cats. Single fields of 45 afferents (conduction velocities = 0.25–4.92 m/s) were identified in the left ventricle with a stimulating electrode. Five minutes of myocardial ischemia stimulated 39 of 45 cardiac afferents (8 Aδ, 37 C fibers). Epicardial application of ATP (1–4 μmol) stimulated six ischemically sensitive cardiac afferents in a dose-dependent manner. Additionally, epicardial ATP (2 μmol), ADP (2 μmol), a P2Y agonist, and α,β-meATP (0.5 μmol) significantly activated eight other ischemically sensitive afferents. Third, pyridoxal phosphate-6-azophenyl-2′,4′-disulfonic acid, a P2 receptor antagonist, abolished the responses of six afferents to epicardial ATP (2 μmol) and attenuated the ischemia-related increase in activity of seven other afferents by 37%. In the absence of P2 receptor blockade, cardiac afferents responded consistently to repeated application of ATP ( n = 6) and to recurrent myocardial ischemia ( n = 6). Finally, six ischemia-insensitive cardiac spinal afferents did not respond to epicardial ATP (2–4 μmol), although these afferents did respond to epicardial bradykinin. Taken together, these data indicate that, during ischemia, endogenously released ATP activates ischemia-sensitive, but not ischemia-insensitive, cardiac spinal afferents through stimulation of P2 receptors likely located on the cardiac sensory neurites.

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