1699-P: Mechanisms and Roles of Foxo1-Akt Negative Feedback Pathway in Adipocytes

Diabetes ◽  
2020 ◽  
Vol 69 (Supplement 1) ◽  
pp. 1699-P
Author(s):  
TOMOHIRO OHNO ◽  
HIRAKU ONO ◽  
KOUTARO YOKOTE
Keyword(s):  
Negative Feedback ◽  
Feedback Pathway

ATP Release from Red Blood Cells Is Regulated by a Negative Feedback Pathway where ADP Acts on P2Y13 Receptors.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 1576-1576
Author(s):  
Martin L. Olsson ◽  
Lingwei Wang ◽  
Goran Olivecrona ◽  
Matthias Gotberg ◽  
Stefan Amisten ◽  
...  
Keyword(s):  
Red Blood Cells ◽  
Negative Feedback ◽  
Blood Cells ◽  
Atp Release ◽  
Pig Model ◽  
Coronary Vein ◽  
Human Red Blood Cells ◽  
Adp Receptor ◽  
Tissue Circulation ◽  
Feedback Pathway

Abstract Background: Red blood cells regulate tissue circulation and O2 delivery by releasing the vasodilator adenosine triphosphate (ATP) in response to hypoxia. When released extracellularly, ATP is rapidly degraded to adenosine diphosphate (ADP) in the circulation by ectonucleotidases. ATP and ADP activate subtypes of the large P2 receptor family (15 subtypes). Here we show that ADP acting on P2Y13 receptors on red blood cells serves as a negative feedback pathway for the inhibition of ATP release. Methods: mRNA was quantified with real-time PCR. Western blot was used to detect P2 receptors with available antibodies. cAMP levels were determined with an enzyme immunoassay. ATP release was measured in incubated red blood cells using microdialysis and a luciferase assay. In a pig model, catheters were inserted through the carotid artery to place a catheter in the left coronary artery, and through the jugular vein to place a microdialysis probe in the coronary vein. 2-MeSADP was injected in the artery and ATP levels were measured in the coronary vein. Results: mRNA of the ADP receptor P2Y13 was highly expressed in human red blood cells and reticulocytes, whilst other ADP receptors were not (Fig.1). Figure Figure The stable ADP analogue 2-MeSADP decreased ATP release from red blood cells by inhibition of cAMP. The P2Y12 and P2Y13 receptor antagonist AR-C67085 (30 mM), but not the P2Y1 blocker MRS2179, inhibited the effects of 2-MeSADP. At doses where AR-C67085 only blocks P2Y12 (100 nM), it had no effect. AR-C67085 and the nucleotidase apyrase increased cAMP per se, indicating a constant cAMP inhibitory effect of endogenous extracellular ADP. 2-MeSADP reduced plasma ATP concentrations in an in vivo pig model. Furthermore, a missense polymorphism in the coding region of P2Y13 has been found that is in total disequilibrium with 5 polymorphisms in P2Y12 (the important ADP receptor in platelets) forming a haplotype that could contribute to vascular disease. Conclusion: Our results show that P2Y13 is selectively expressed in human red blood cells. The ATP degradation product ADP inhibited ATP release by acting on this receptor. This negative feedback system could be important in the control of plasma ATP levels and tissue circulation. Because blood consists of approximately 40% red blood cells, containing a 1000-fold higher ATP concentration than plasma (mM vs. uM), even a minor release of ATP from the high intracellular concentrations could have major circulatory effects. A negative system may therefore be of great physiological importance to mitigate ATP release. In addition, this finding could be of interest for efforts to preserve intracellular ATP in red blood cells during storage.

Integrin-αIIbβ3-mediated outside-in signalling activates a negative feedback pathway to suppress platelet activation

2016 ◽  
Vol 116 (11) ◽  
pp. 918-930 ◽  
Author(s):  
Baiyun Dai ◽  
Peng Wu ◽  
Feng Xue ◽  
Renchi Yang ◽  
Ziqiang Yu ◽  
...  
Keyword(s):  
Flow Cytometry ◽  
Platelet Activation ◽  
Negative Feedback ◽  
Human Platelets ◽  
Wild Type ◽  
Integrin Αiibβ3 ◽  
Atp Secretion ◽  
Platelet Disaggregation ◽  
Feedback Pathway

SummaryIntegrin-αIIbβ3-mediated outside-in signalling is widely accepted as an amplifier of platelet activation; accumulating evidence suggests that outside-in signalling can, under certain conditions, also function as an inhibitor of platelet activation. The role of integrin-αIIbβ3-mediated outside-in signalling in platelet activation is disputable. We employed flow cytometry, aggregometry, immunoprecipitation, and immunoblotting to investigate the role of integrin-αIIbβ3-mediated outside-in signalling in platelet activation. Integrin αIIbβ3 inhibition enhances agonist-induced platelet ATP secretion. Human platelets lacking expression of αIIbβ3 exhibited more platelet ATP secretion than their wild-type counterparts. Moreover, integrin-αIIbβ3-mediated outside-in signals activate SHIP-1, which in turn mediates p-Akt dep-hosphorylation, leading to inactivation of PI3K/Akt signalling. Furthermore, 3AC (SHIP-1 inhibitor) inhibits platelet disaggregation, and promotes platelet ATP secretion. Upon ADP stimulation, Talin is recruited to αIIbβ3, and it is dissociated from αIIbβ3 when platelets disaggregate. In addition, treatment with RUC2, an inhibitor of αIIbβ3, which blocks αIIbβ3-mediated outside-in signalling, can markedly prevent the dissociation of talin from integrin. SHIP1 Inhibitor 3AC inhibits the dissociation of talin from integrin-β3. These results suggest that integrin-αIIbβ3-mediated outside-in signalling can serve as a brake to restrict unnecessary platelet activation by activated SHIP-1, which mediated the disassociation of talin from β3, leading to integrin inactivation and blocking of PI3K/Akt signalling to restrict platelet ATP secretion.

A horizontal cell selectively contacts blue-sensitive cones in cyprinid fish retina : intracellular staining with horseradish peroxidase

1988 ◽  
Vol 235 (1280) ◽  
pp. 281-287 ◽  
Keyword(s):  
Horseradish Peroxidase ◽  
Negative Feedback ◽  
Horizontal Cell ◽  
Cyprinid Fish ◽  
Horizontal Cells ◽  
Intracellular Staining ◽  
Yellow Orange ◽  
Fish Retina ◽  
Feedback Pathway

A horizontal cell selectively contacting blue-sensitive cones has been intracellularly stained with horseradish peroxidase in the retina of a cyprinid fish, the roach. The light microscopical morphology of the cell belonged to the H3 category of horizontal cells found in cyprinid fish retinae. In response to spectral stimuli, the cell generated chromaticity-type S-potentials that were hyperpolarizing to blue and depolarizing to yellow-orange. A red-sensitive hyperpolarizing component was absent possibly because of suppression of the negative feedback pathway between luminosity-type (H1) horizontal cells and green-sensitive cones.

scholarly journals N-myc downstream-regulated gene 2 inhibits human cholangiocarcinoma progression and is regulated by leukemia inhibitory factor/MicroRNA-181c negative feedback pathway

Hepatology ◽  
2016 ◽  
Vol 64 (5) ◽  
pp. 1606-1622 ◽  
Author(s):  
Jiabei Wang ◽  
Changming Xie ◽  
Shangha Pan ◽  
Yingjian Liang ◽  
Jihua Han ◽  
...  
Keyword(s):  
Negative Feedback ◽  
Leukemia Inhibitory Factor ◽  
Inhibitory Factor ◽  
Feedback Pathway

Neural interactions between cone photoreceptors and horizontal cells in the turtle (Mauremys caspica) retina

1998 ◽  
Vol 15 (1) ◽  
pp. 1-13 ◽  
Author(s):  
HUSAM ASI ◽  
IDO PERLMAN
Keyword(s):  
Negative Feedback ◽  
Cascade Model ◽  
Horizontal Cells ◽  
Cone Photoreceptors ◽  
Action Spectra ◽  
Inhibitory Feedback ◽  
Neural Interactions ◽  
Chromatic Properties ◽  
Feedback Pathway ◽  
Mauremys Caspica

Horizontal cells and cone photoreceptors in the vertebrate retina are interconnected by a complex network of synapses leading to the generation of color-coded responses in chromaticity horizontal cells. A simple cascade model of excitatory feedforward and inhibitory feedback synapses had been suggested to underlie these observations. In this study, the photoresponses of cones and horizontal cells were recorded intracellularly from the turtle eyecup. Three different approaches were adopted in order to test quantitatively the cascade model. Comparing linearity functions between these neurons indicated multiple excitatory inputs to each type of horizontal cells. The depolarizing photoresponses of R/G C-type horizontal cells were considerably faster than those of L-type horizontal cells but slower than those recorded from L-cones. This observation disagrees with the basic assumption of the cascade model that assign the depolarizing photoresponses of R/G C-type horizontal cells to a negative feedback pathway from L-type horizontal cells onto M-cones. Finally, the action spectra of each of the three types of horizontal cells could not be solely accounted for by input from one spectral type of cones. Only by assuming excitatory and inhibitory inputs from all spectral types of cones, the action spectra of all types of horizontal cells could be reconstructed. These findings suggest that the negative feedback pathways from horizontal cells onto cones in the turtle retina cannot solely account for the chromatic properties of the horizontal cells and support a direct inhibitory inputs from cones to turtle horizontal cells.

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