scholarly journals An antiangiogenic neurokinin-B/thromboxane A2 regulatory axis

2006 ◽  
Vol 174 (7) ◽  
pp. 1047-1058 ◽  
Author(s):  
Saumen Pal ◽  
Jing Wu ◽  
Justin K. Murray ◽  
Samuel H. Gellman ◽  
Michele A. Wozniak ◽  
...  
Keyword(s):  
Vascular Remodeling ◽  
Cellular Proliferation ◽  
Chorioallantoic Membrane ◽  
Growth Factor Receptor ◽  
Cyclic Adenosine Monophosphate ◽  
Adenosine Monophosphate ◽  
Receptor Expression ◽  
Complex Signal ◽  
Neurokinin B ◽  
Vessel Development

Establishment of angiogenic circuits that orchestrate blood vessel development and remodeling requires an exquisite balance between the activities of pro- and antiangiogenic factors. However, the logic that permits complex signal integration by vascular endothelium is poorly understood. We demonstrate that a “neuropeptide,” neurokinin-B (NK-B), reversibly inhibits endothelial cell vascular network assembly and opposes angiogenesis in the chicken chorioallantoic membrane. Disruption of endogenous NK-B signaling promoted angiogenesis. Mechanistic analyses defined a multicomponent pathway in which NK-B signaling converges upon cellular processes essential for angiogenesis. NK-B−mediated ablation of Ca2+ oscillations and elevation of 3′–5′ cyclic adenosine monophosphate (cAMP) reduced cellular proliferation, migration, and vascular endothelial growth factor receptor expression and induced the antiangiogenic protein calreticulin. Whereas NK-B initiated certain responses, other activities required additional stimuli that increase cAMP. Although NK-B is a neurotransmitter/ neuromodulator and NK-B overexpression characterizes the pregnancy-associated disorder preeclampsia, NK-B had not been linked to vascular remodeling. These results establish a conserved mechanism in which NK-B instigates multiple activities that collectively oppose vascular remodeling.

scholarly journals Changes in cAMP effector predominance are associated with increased oxytocin receptor expression in twin but not infection-associated or idiopathic preterm labour

PLoS ONE ◽  
2020 ◽  
Vol 15 (11) ◽  
pp. e0240325
Author(s):  
Angela Yulia ◽  
Alice J. Varley ◽  
Natasha Singh ◽  
Kaiyu Lei ◽  
Rachel Tribe ◽  
...  
Keyword(s):  
Preterm Labour ◽  
Cyclic Adenosine Monophosphate ◽  
Adenosine Monophosphate ◽  
Oxytocin Receptor ◽  
Receptor Expression ◽  
Mrna Levels ◽  
Effector Pathway ◽  
Effector System ◽  
Term Labour ◽  
Camp Levels

We previously reported that at term pregnancy, a decline in myometrial protein kinase A (PKA) activity leads to an exchange protein activated by cyclic AMP (Epac1)-dependent increase in oxytocin receptor (OTR) expression, promoting the onset of labour. Here, we studied the changes in the cyclic adenosine monophosphate (cAMP) effector system present in different phenotypes of preterm labour (PTL). Myometrial biopsies obtained from women with phenotypically distinct forms of PTL and the levels of PKA and OTR were examined. Although we found similar changes in the cAMP effector pathway in all forms of PTL, only in the case of twin PTL (T-PTL) was myometrial OTR levels increased in association with these results. Although there were several changes in the mRNA levels of components of the cAMP synthetic pathway, the total myometrial cAMP levels did not change with the onset of any subtype of PTL. With regards to the expression of cAMP-responsive genes, we found that the mRNA levels of 4 of the 5 cAMP-down-regulated genes were increased in T-PTL, similar to our findings in term labour. These data signify that although changes in the cAMP effector system were common to all forms of PTL, only in T-PTL were OTR levels increased. Similarly, the mRNA levels of cAMP-repressed genes were only increased in T-PTL supporting the concept that the decline in PKA levels influences myometrial function driving the onset of T-PTL.

scholarly journals Therapeutic melanoma inhibition by local micelle-mediated cyclic nucleotide repression

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Kerstin Johann ◽  
Toszka Bohn ◽  
Fatemeh Shahneh ◽  
Natascha Luther ◽  
Alexander Birke ◽  
...  
Keyword(s):  
Immune Cells ◽  
Antitumor Immunity ◽  
Immune Escape ◽  
Cyclic Adenosine Monophosphate ◽  
Adenosine Monophosphate ◽  
Benzyl Ester ◽  
Receptor Expression ◽  
Single Cell Sequencing ◽  
Copolymer Micelles ◽  
Toxic Concentrations

AbstractThe acidic tumor microenvironment in melanoma drives immune evasion by up-regulating cyclic adenosine monophosphate (cAMP) in tumor-infiltrating monocytes. Here we show that the release of non-toxic concentrations of an adenylate cyclase (AC) inhibitor from poly(sarcosine)-block-poly(L-glutamic acid γ-benzyl ester) (polypept(o)id) copolymer micelles restores antitumor immunity. In combination with selective, non-therapeutic regulatory T cell depletion, AC inhibitor micelles achieve a complete remission of established B16-F10-OVA tumors. Single-cell sequencing of melanoma-infiltrating immune cells shows that AC inhibitor micelles reduce the number of anti-inflammatory myeloid cells and checkpoint receptor expression on T cells. AC inhibitor micelles thus represent an immunotherapeutic measure to counteract melanoma immune escape.

Fibroblast growth factor receptor expression in aural polyps: predictor of cholesteatoma?

2004 ◽  
Vol 118 (5) ◽  
pp. 338-342 ◽  
Author(s):  
Salil Nair ◽  
Simon Watts ◽  
Liam Flood
Keyword(s):  
Growth Factor ◽  
Fibroblast Growth Factor ◽  
Wound Repair ◽  
Cellular Proliferation ◽  
Nuclear Translocation ◽  
Growth Factor Receptor ◽  
Staining Intensity ◽  
Receptor Expression ◽  
Fibroblast Growth ◽  
Middle Ear Mucosa

The cytokine, fibroblast growth factor (FGF) and its receptors (FGFR) have a pivotal role in wound repair and have been demonstrated in the perimatrix of active cholesteatoma. Aural polyps are a recognized inflammatory reaction of middle-ear mucosa to cholesteatoma, but may arise in its absence. This study examines 28 archival aural polyp specimens, seeking an increased expression for FGFR1 and FGFR3 in polyps associated with cholesteatoma, when compared with those arising in non-cholesteatomatous, mucosal disease, but produced a null result. There was no difference demonstrated in staining intensity between those polyps associated with cholesteatoma and those without. There was a strong correlation between staining patterns of FGFR1 and FGFR3 (r = 0.4, p <0.03). The expression pattern, of nuclear and perinuclear localization, may support the view that nuclear translocation of growth factors, and their receptors, could be related to the cellular proliferation that is associated with cholesteatoma.

Red Blood Cell Surface Receptor Expression of BCAM/Lu is Regulated by Protein Kinase A Activity

2013 ◽  
Author(s):  
J. L. Maciaszek ◽  
B. Andemariam ◽  
G. Lykotrafitis
Keyword(s):  
Protein Kinase ◽  
Protein Kinase A ◽  
Cyclic Adenosine Monophosphate ◽  
Adenosine Monophosphate ◽  
Receptor Expression ◽  
Cell Surface Receptor ◽  
Intermediate Step ◽  
Surface Receptors ◽  
Surface Receptor ◽  
Kinase A

Irregular sickle red blood cells (RBCs) can contribute to the pathogenesis of vasoocclusion and other complications of sickle cell disease (SCD) via abnormal adherence to the vascular endothelium. It has previously been demonstrated that epinephrine enhances SCD RBC adhesion by activating the BCAM/Lu and ICAM-4 surface receptors [1–2]. Epinephrine acts on the RBC β2-adrenergic receptor, thereby activating Gas proteins that stimulate adenylyl cyclase (AC). This enzyme catalyzes the conversion of adenosine triphosphate (ATP) to cyclic adenosine monophosphate (cAMP), leading to protein kinase A (PKA) activation, an intermediate step in the upregulation of BCAM/Lu and ICAM-4 mediated adhesion. The interaction of BCAM/Lu with the α5 chain of laminin may contribute to vaso-occlusive events in SCD due to overexpression of BCAM on SCD RBCs.

scholarly journals GPR18 undergoes a high degree of constitutive trafficking but is unresponsive to N-Arachidonoyl Glycine

PeerJ ◽  
2016 ◽  
Vol 4 ◽  
pp. e1835 ◽  
Author(s):  
David B. Finlay ◽  
Wayne R. Joseph ◽  
Natasha L. Grimsey ◽  
Michelle Glass
Keyword(s):  
Cell Lines ◽  
Membrane Trafficking ◽  
Cannabinoid Receptor ◽  
Signal Sequence ◽  
Cyclic Adenosine Monophosphate ◽  
Adenosine Monophosphate ◽  
Receptor Expression ◽  
Cellular Migration ◽  
Orphan Receptor ◽  
Cell Surface Expression

The orphan receptor GPR18 has become a research target following the discovery of a putative endogenous agonist, N-arachidonoyl glycine (NAGly). Chemical similarity between NAGly and the endocannabinoid anandamide suggested the hypothesis that GPR18 is a third cannabinoid receptor. GPR18-mediated cellular signalling through inhibition of cyclic adenosine monophosphate (cAMP) and phosphorylation of extracellular signal-regulated kinase (ERK), in addition to physiological consequences such as regulation of cellular migration and proliferation/apoptosis have been described in response to both NAGly and anandamide. However, discordant findings have also been reported. Here we sought to describe the functional consequences of GPR18 activation in heterologously-expressing HEK cells. GPR18 expression was predominantly intracellular in stably transfected cell lines, but moderate cell surface expression could be achieved in transiently transfected cells which also had higher overall expression. Assays were employed to characterise the ability of NAGly or anandamide to inhibit cAMP or induce ERK phosphorylation through GPR18, or induce receptor trafficking. Positive control experiments, which utilised cells expressing hCB1 receptors (hCB1R), were performed to validate assay design and performance. While these functional pathways in GPR18-expressing cells were not modified on treatment with a panel of putative GPR18 ligands, a constitutive phenotype was discovered for this receptor. Our data reveal that GPR18 undergoes rapid constitutive receptor membrane trafficking—several-fold faster than hCB1R, a highly constitutively active receptor. To enhance the likelihood of detecting agonist-mediated receptor signalling responses, we increased GPR18 protein expression (by tagging with a preprolactin signal sequence) and generated a putative constitutively inactive receptor by mutating the hGPR18 gene at amino acid site 108 (alanine to asparagine). This A108N mutant did cause an increase in surface receptor expression (which may argue for reduced constitutive activity), but no ligand-mediated effects were detected. Two glioblastoma multiforme cell lines (which endogenously express GPR18) were assayed for NAGly-induced pERK phosphorylation, with negative results. Despite a lack of ligand-mediated responses in all assays, the constitutive trafficking of GPR18 remains an interesting facet of receptor function and will have consequences for understanding the role of GPR18 in physiology.

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