scholarly journals Differential Signaling Profiles of MC4R Mutations with Three Different Ligands

2020 ◽  
Vol 21 (4) ◽  
pp. 1224 ◽  
Author(s):  
Sarah Paisdzior ◽  
Ioanna Maria Dimitriou ◽  
Paul Curtis Schöpe ◽  
Paolo Annibale ◽  
Patrick Scheerer ◽  
...  
Keyword(s):  
Signaling Pathways ◽  
G Protein ◽  
Cyclic Adenosine Monophosphate ◽  
Adenosine Monophosphate ◽  
Loss Of Function ◽  
Melanocyte Stimulating Hormone ◽  
Melanocortin 4 Receptor ◽  
Erk Phosphorylation ◽  
Extracellular Regulated Kinase ◽  
Peptide Agonist

The melanocortin 4 receptor (MC4R) is a key player in hypothalamic weight regulation and energy expenditure as part of the leptin–melanocortin pathway. Mutations in this G protein coupled receptor (GPCR) are the most common cause for monogenetic obesity, which appears to be mediated by changes in the anorectic action of MC4R via GS-dependent cyclic adenosine-monophosphate (cAMP) signaling as well as other signaling pathways. To study potential bias in the effects of MC4R mutations between the different signaling pathways, we investigated three major MC4R mutations: a GS loss-of-function (S127L) and a GS gain-of-function mutant (H158R), as well as the most common European single nucleotide polymorphism (V103I). We tested signaling of all four major G protein families plus extracellular regulated kinase (ERK) phosphorylation and β-arrestin2 recruitment, using the two endogenous agonists, α- and β-melanocyte stimulating hormone (MSH), along with a synthetic peptide agonist (NDP-α-MSH). The S127L mutation led to a full loss-of-function in all investigated pathways, whereas V103I and H158R were clearly biased towards the Gq/11 pathway when challenged with the endogenous ligands. These results show that MC4R mutations can cause vastly different changes in the various MC4R signaling pathways and highlight the importance of a comprehensive characterization of receptor mutations.

scholarly journals Determination of the melanocortin-4 receptor structure identifies Ca2+ as a cofactor for ligand binding

Science ◽  
2020 ◽  
Vol 368 (6489) ◽  
pp. 428-433 ◽  
Author(s):  
Jing Yu ◽  
Luis E. Gimenez ◽  
Ciria C. Hernandez ◽  
Yiran Wu ◽  
Ariel H. Wein ◽  
...  
Keyword(s):  
G Protein ◽  
Energy Homeostasis ◽  
Cyclic Adenosine Monophosphate ◽  
Adenosine Monophosphate ◽  
Peptide Ligand ◽  
Melanocyte Stimulating Hormone ◽  
Melanocortin 4 Receptor ◽  
Syndromic Obesity ◽  
G Protein Coupled

The melanocortin-4 receptor (MC4R) is involved in energy homeostasis and is an important drug target for syndromic obesity. We report the structure of the antagonist SHU9119-bound human MC4R at 2.8-angstrom resolution. Ca2+ is identified as a cofactor that is complexed with residues from both the receptor and peptide ligand. Extracellular Ca2+ increases the affinity and potency of the endogenous agonist α-melanocyte–stimulating hormone at the MC4R by 37- and 600-fold, respectively. The ability of the MC4R crystallized construct to couple to ion channel Kir7.1, while lacking cyclic adenosine monophosphate stimulation, highlights a heterotrimeric GTP-binding protein (G protein)–independent mechanism for this signaling modality. MC4R is revealed as a structurally divergent G protein–coupled receptor (GPCR), with more similarity to lipidic GPCRs than to the homologous peptidic GPCRs.

scholarly journals GPRC5A: An Emerging Biomarker in Human Cancer

2018 ◽  
Vol 2018 ◽  
pp. 1-11 ◽  
Author(s):  
Xiaoxia Jiang ◽  
Xin Xu ◽  
Mengjie Wu ◽  
Zhonghai Guan ◽  
Xingyun Su ◽  
...  
Keyword(s):  
Signaling Pathways ◽  
G Protein ◽  
Molecular Mechanisms ◽  
Lung Tumor ◽  
Human Cancer ◽  
Cyclic Adenosine Monophosphate ◽  
Adenosine Monophosphate ◽  
Aberrant Expression ◽  
Human Cancers ◽  
G Protein Coupled

Aberrant expression of G protein-coupled receptors (GPCRs) is frequently associated with tumorigenesis. G Protein-coupled receptor class C group 5 member A (GPRC5A) is a member of the GPCR superfamily, is expressed preferentially in lung tissues, and is regulated by various entities at multiple levels. GPRC5A exerts a tumor suppressive role in lung cancer and GPRC5A deletion promotes lung tumor initiation and progression. Recent advances have highlighted that GPRC5A dysregulation is found in various human cancers and is related to many tumor-associated signaling pathways, including the cyclic adenosine monophosphate (cAMP), nuclear factor (NF)-κB, signal transducer and activator of transcription (STAT) 3, and focal adhesion kinase (FAK)/Src signaling. This review aimed to summarize our updated view on the biology and regulation of GPRC5A, its expression in human cancers, and the linked signaling pathways. A better comprehension of the underlying cellular and molecular mechanisms of GPRC5A will provide novel insights into its potential diagnostic and therapeutic value.

Protein kinase Cζ mediated Raf-1/extracellular-regulated kinase activation by daunorubicin

Blood ◽  
2003 ◽  
Vol 101 (4) ◽  
pp. 1543-1550 ◽  
Author(s):  
Véronique Mansat-De Mas ◽  
Hélène Hernandez ◽  
Isabelle Plo ◽  
Christine Bezombes ◽  
Nicolas Maestre ◽  
...  
Keyword(s):  
Protein Kinase ◽  
Mapk Pathway ◽  
Cyclic Adenosine Monophosphate ◽  
Adenosine Monophosphate ◽  
Mek Inhibitor ◽  
Mapk Signaling ◽  
Mitogen Activated Protein Kinase ◽  
Protective Function ◽  
Erk Phosphorylation ◽  
Extracellular Regulated Kinase

In light of the emerging concept of a protective function of the mitogen-activated protein kinase (MAPK) pathway under stress conditions, we investigated the influence of the anthracycline daunorubicin (DNR) on MAPK signaling and its possible contribution to DNR-induced cytotoxicity. We show that DNR increased phosphorylation of extracellular-regulated kinases (ERKs) and stimulated activities of both Raf-1 and extracellular-regulated kinase 1 (ERK1) within 10 to 30 minutes in U937 cells. ERK1 stimulation was completely blocked by either the mitogen-induced extracellular kinase (MEK) inhibitor PD98059 or the Raf-1 inhibitor 8-bromo-cAMP (cyclic adenosine monophosphate). However, only partial inhibition of Raf-1 and ERK1 stimulation was observed with the antioxidant N-acetylcysteine (N-Ac). Moreover, the xanthogenate compound D609 that inhibits DNR-induced phosphatidylcholine (PC) hydrolysis and subsequent diacylglycerol (DAG) production, as well as wortmannin that blocks phosphoinositide-3 kinase (PI3K) stimulation, only partially inhibited Raf-1 and ERK1 stimulation. We also observed that DNR stimulated protein kinase C ζ (PKCζ), an atypical PKC isoform, and that both D609 and wortmannin significantly inhibited DNR-triggered PKCζ activation. Finally, we found that the expression of PKCζ kinase-defective mutant resulted in the abrogation of DNR-induced ERK phosphorylation. Altogether, these results demonstrate that DNR activates the classical Raf-1/MEK/ERK pathway and that Raf-1 activation is mediated through complex signaling pathways that involve at least 2 contributors: PC-derived DAG and PI3K products that converge toward PKCζ. Moreover, we show that both Raf-1 and MEK inhibitors, as well as PKCζ inhibition, sensitized cells to DNR-induced cytotoxicity.

Effects of hormones on 3', 5' -cyclic adenosine monophosphate in choroid plexus.

1977 ◽  
Vol 232 (4) ◽  
pp. E353
Author(s):  
D Rudman ◽  
B M Hollins ◽  
N C Lewis ◽  
J W Scott
Keyword(s):  
Effective Dose ◽  
Choroid Plexus ◽  
Cyclic Adenosine Monophosphate ◽  
Adenosine Monophosphate ◽  
Tyrode Solution ◽  
Minimal Effective Dose ◽  
Camp Content ◽  
Melanocyte Stimulating Hormone ◽  
Stimulating Hormone

Choroid plexus of rabbit and rat was incubated for 2-30 min at 37 degrees C under 95% O2-5% CO2 in Tyrode solution containing 10 mM glucose and 1 mM theophylline with these agents: epinephrine, norepinephrine, isoproterenol, dopamine, histamine, serotonin, arginine, and lysine vasopressins, oxytocin, angiotensin, adrenocorticotropin (ACTH), beta-melanocyte-stimulating hormone, and choroid plexus peptide IIF. After incubation, tissue and medium were analyzed for 3', 5' -cyclic adenosine monophosphate (cAMP) content. Each amine or peptide was tested initially at 1,000 microng/ml. Only ACTH and serotonin affected cAMP content of rabbit choroid plexus. At 1,000 microng/ml, these agents caused a 10 and 4 times (respectively) increase in cAMP content of tissue + medium at 2-10 min with decline in content at 10-30 min. More than 90% of the increment was located in tissue, less than 10% in medium. Minimal effective dose (MED) to cause a significant (P less than .05) accumulation of cAMP was 0.1 microng/ml (2.2 x 10(-8) M) for ACTH and 10 microng/ml (5.7 x10(-3) M) for serotonin. Only isoproterenol, epinephrine, and norepinephrine influenced cAMP content of rat choroid plexus. MED's for this effect by isoproterenol, epinephrine, and norepinephrine were .001, .01, and 10 microng/ml (4.7 x 10(-9), 5.5 x 10(-8), and 5.9 x 10(-5) M), respectively.

scholarly journals Rottlerin Reduces cAMP/CREB-Mediated Melanogenesis via Regulation of Autophagy

2019 ◽  
Vol 20 (9) ◽  
pp. 2081 ◽  
Author(s):  
Nurinanda Prisky Qomaladewi ◽  
Mi-Yeon Kim ◽  
Jae Youl Cho
Keyword(s):  
Signaling Pathway ◽  
Cyclic Adenosine Monophosphate ◽  
Adenosine Monophosphate ◽  
Camp Response Element Binding ◽  
Sequential Process ◽  
Camp Response Element ◽  
Melanin Production ◽  
Melanocyte Stimulating Hormone ◽  
Cellular Autophagy

Melanogenesis is the sequential process of melanin production by melanocytes in order to protect the skin from harmful stimuli. Melanogenesis is disrupted by radiation exposure, which results in the differentiation of melanocytes into melanoma. Recently, some methods have been developed to maintain the instability of melanogenesis in melanoma by activating cellular autophagy. However, there is still a lack of knowledge about how autophagy is involved in the regulation of melanogenesis in melanoma cells. Here, we used rottlerin as an autophagy inducer to investigate the role of the cyclic adenosine monophosphate (cAMP)/cAMP response element binding (CREB) signaling pathway in melanogenesis. We found that rottlerin can inhibit melanin production by targeting cAMP, which is initially activated by alpha-melanocyte stimulating hormone (α-MSH). Our findings suggest that rottlerin has a pivotal role as an autophagy inducer in the regulation of melanogenesis by targeting the cAMP/CREB signaling pathway.

Investigation of distinct molecular pathways in migraine induction using calcitonin gene-related peptide and sildenafil

Cephalalgia ◽  
2019 ◽  
Vol 39 (14) ◽  
pp. 1776-1788 ◽  
Author(s):  
Samaira Younis ◽  
Casper E Christensen ◽  
Nikolaj M Toft ◽  
Thomas Søborg ◽  
Faisal M Amin ◽  
...  
Keyword(s):  
Signaling Pathways ◽  
Intracellular Signaling ◽  
Cyclic Adenosine Monophosphate ◽  
Adenosine Monophosphate ◽  
Cyclic Guanosine Monophosphate ◽  
Calcitonin Gene Related Peptide ◽  
Guanosine Monophosphate ◽  
Related Peptide ◽  
Intracellular Signaling Pathways ◽  
Calcitonin Gene

Objective Migraine displays clinical heterogeneity of attack features and attack triggers. The question is whether this heterogeneity is explained by distinct intracellular signaling pathways leading to attacks with distinct clinical features. One well-known migraine-inducing pathway is mediated by cyclic adenosine monophosphate and another by cyclic guanosine monophosphate. Calcitonin gene-related peptide triggers migraine via the cyclic adenosine monophosphate pathway and sildenafil via the cyclic guanosine monophosphate pathway. To date, no studies have examined whether migraine induction mediated via the cyclic adenosine monophosphate and cyclic guanosine monophosphate pathways yields similar attacks within the same patients. Methods Patients were subjected to migraine induction on two separate days using calcitonin gene-related peptide (1.5 µg/min for 20 minutes) and sildenafil (100 mg) in a double-blind, randomized, double-dummy, cross-over design. Data on headache intensity, characteristics and accompanying symptoms were collected until 24 hours after drug administration. Results Thirty-four patients were enrolled and 27 completed both study days. Seventeen patients developed migraine after both study drugs (63%; 95% CI: 42–81). Eight patients developed migraine on one day only (seven after sildenafil and one after calcitonin gene-related peptide). Two patients did not develop migraine on either day. Headache laterality, nausea, photophobia and phonophobia were similar between drugs in 77%, 65%, 100%, and 94%, respectively, of the 17 patients who developed attacks on both days. Conclusion A majority of patients developed migraine after both calcitonin gene-related peptide and sildenafil. This supports the hypothesis that the cyclic adenosine monophosphate and cyclic guanosine monophosphate intracellular signaling pathways in migraine induction converge in a common cellular determinator, which ultimately triggers the same attacks. Trial registration: ClinicalTrials.gov Identifier: NCT03143465.

scholarly journals Adenosine and Forskolin Inhibit Platelet Aggregation by Collagen but not the Proximal Signalling Events

2019 ◽  
Vol 119 (07) ◽  
pp. 1124-1137 ◽  
Author(s):  
Joanne C. Clark ◽  
Deirdre M. Kavanagh ◽  
Stephanie Watson ◽  
Jeremy A. Pike ◽  
Robert K. Andrews ◽  
...  
Keyword(s):  
Adenylyl Cyclase ◽  
G Protein ◽  
Platelet Activation ◽  
Cyclic Adenosine Monophosphate ◽  
Adenosine Monophosphate ◽  
Adenosine Diphosphate ◽  
Receptor Activation ◽  
Inhibitory Effect ◽  
Human Platelets ◽  
Adenosine Receptor Agonist

Background The G protein-coupled receptor, adenosine A2A, signals through the stimulatory G protein, Gs, in platelets leading to activation of adenylyl cyclase and elevation of cyclic adenosine monophosphate (cAMP) and inhibition of platelet activation. Objective This article investigates the effect of A2A receptor activation on signalling by the collagen receptor glycoprotein (GP) VI in platelets. Methods Washed human platelets were stimulated by collagen or the GPVI-specific agonist collagen-related peptide (CRP) in the presence of the adenosine receptor agonist, 5′-N-ethylcarboxamidoadenosine (NECA) or the adenylyl cyclase activator, forskolin and analysed for aggregation, adenosine triphosphate secretion, protein phosphorylation, spreading, Ca2+ mobilisation, GPVI receptor clustering, cAMP, thromboxane B2 (TxB2) and P-selectin exposure. Results NECA, a bioactive adenosine analogue, partially inhibits aggregation and secretion to collagen or CRP in the absence or presence of the P2Y12 receptor antagonist, cangrelor and the cyclooxygenase inhibitor, indomethacin. The inhibitory effect in the presence of the three inhibitors is largely overcome at higher concentrations of collagen but not CRP. Neither NECA nor forskolin altered clustering of GPVI, elevation of Ca2+ or spreading of platelets on a collagen surface. Further, neither NECA nor forskolin, altered collagen-induced tyrosine phosphorylation of Syk, LAT nor PLCγ2. However, NECA and forskolin inhibited platelet activation by the TxA2 mimetic, U46619, but not the combination of adenosine diphosphate and collagen. Conclusion NECA and forskolin have no effect on the proximal signalling events by collagen. They inhibit platelet activation in a response-specific manner in part through inhibition of the feedback action of TxA2.

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