RESUMEN
The two-kidney, one-clip (2K1C) Goldblatt rodent model elicits a reduction in renal blood flow (RBF) in the clipped kidney (CK). The reduced RBF and oxygen bio-ability causes the accumulation of the tricarboxylic cycle intermediary, α-ketoglutarate, which activates the oxoglutarate receptor-1 (OXGR1). In the kidney, OXGR1 is abundantly expressed in intercalated cells (ICs) of the collecting duct (CD), thus contributing to sodium transport and electrolyte balance. The (pro)renin receptor (PRR), a member of the renin-angiotensin system (RAS), is a key regulator of sodium reabsorption and blood pressure (BP) that is expressed in ICs. The PRR is upregulated in 2K1C rats. Here, we tested the hypothesis that chronic reduction in RBF in the CK leads to OXGR1-dependent PRR upregulation in the CD and alters sodium balance and BP in 2K1C mice. To determine the role of OXGR1 in regulating the PRR in the CDs during renovascular hypertension, we performed 2K1C Goldblatt surgery (clip = 0.13 mm internal gap, 14 days) in two groups of male mice: (1) mice treated with Montelukast (OXGR1 antagonist; 5 mg/Kg/day); (2) OXGR1-/- knockout mice. Wild-type and sham-operated mice were used as controls. After 14 days, 2K1C mice showed increased systolic BP (SBP) (108 ± 11 vs. control 82 ± 5 mmHg, p < 0.01) and a lower natriuretic response after the saline challenge test. The CK group showed upregulation of erythropoietin, augmented α-ketoglutarate, and increased PRR expression in the renal medulla. The CK of OXGR1 knockout mice and mice subjected to the OXGR1 antagonist elicited impaired PRR upregulation, attenuated SBP, and better natriuretic responses. In 2K1C mice, the effect of reduced RBF on the OXGR1-dependent PRR upregulation in the CK may contribute to the anti-natriuretic and increased SBP responses.
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Túbulos Renales Colectores , Receptores de Superficie Celular , Sodio , Regulación hacia Arriba , Animales , Ratones , Túbulos Renales Colectores/metabolismo , Receptores de Superficie Celular/metabolismo , Receptores de Superficie Celular/genética , Masculino , Sodio/metabolismo , Hipertensión Renovascular/metabolismo , Hipertensión Renovascular/genética , Presión Sanguínea , Ratones Noqueados , Receptor de Prorenina , Riñón/metabolismo , Modelos Animales de Enfermedad , Sistema Renina-Angiotensina , Ratones Endogámicos C57BL , Receptores Acoplados a Proteínas G/metabolismo , Receptores Acoplados a Proteínas G/genética , Receptores Purinérgicos P2RESUMEN
Luminal breast cancer has a high incidence worldwide and poses a severe health threat. Estrogen receptor alpha (ER-α) is activated by 17ß-estradiol (E2), and its overexpression promotes cancerous characteristics. Luminal breast cancer is an epithelial type; however, the cytokine IL-6, secreted by cells within the tumor microenvironment, stimulates the epithelial-to-mesenchymal transition (EMT) and promotes metastasis. Also, IL-6 decreases ER-α levels, favoring the tamoxifen (TMX) resistance development. However, genes under E2 regulation continue to be expressed even though this receptor is absent. GPR30 is an alternative E2 receptor present in both luminal and aggressive triple-negative breast cancer and is related to TMX resistance and cancer progression. The roles of GPR30 and IL-6 in metastasis have been individually established; however, their interplay remains unexplored. This study aims to elucidate the role of GPR30 in IL-6-induced metastatic properties of MCF-7 luminal breast cancer cells. Results showed that GPR30 contributes to the E2-induced MCF-7 proliferation because its inhibition with the antagonist G15 and the Pertussis toxin (PTX) reduced it. Besides, GPR30 upregulated vimentin and downregulated E-cadherin levels in MCF-7 and TMX-resistant (R-TMX) cells and is also involved in the IL-6-induced migration, invasion, and TMX resistance in MCF-7 cells. In addition, in MDA-MB-231 triple-negative cells, both basal and IL-6-induced metastatic properties were related to GPR30 activity. These results indicate that the GPR30 receptor regulates the EMT induced by IL-6 in breast cancer cells.
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Neoplasias de la Mama , Transición Epitelial-Mesenquimal , Interleucina-6 , Receptores de Estrógenos , Receptores Acoplados a Proteínas G , Humanos , Interleucina-6/metabolismo , Interleucina-6/genética , Receptores Acoplados a Proteínas G/metabolismo , Receptores Acoplados a Proteínas G/genética , Receptores de Estrógenos/metabolismo , Femenino , Transición Epitelial-Mesenquimal/efectos de los fármacos , Neoplasias de la Mama/metabolismo , Neoplasias de la Mama/patología , Neoplasias de la Mama/genética , Células MCF-7 , Movimiento Celular/efectos de los fármacos , Metástasis de la Neoplasia , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Tamoxifeno/farmacología , Proliferación Celular/efectos de los fármacosRESUMEN
Alamandine is a peptide hormone belonging to the renin-angiotensin system (RAS). It acts through the Mas-related G-protein coupled receptor type D, MrgD, which is expressed in different tissues, including the brain. In the present study, we hypothesize that a lack of alamandine, through MrgD, could cause the anxiety-like behavior in transgenic rats with low brain angiotensinogen [TGR(ASrAOGEN)680]. Adult male transgenic rats exhibited a significant increase in the latency to feeding time in the novelty suppressed feeding test and a decrease in the percentage of time and entries in the open arms in the elevated plus maze. These effects were reversed by intracerebroventricular infusion of alamandine. Pretreatment with D-Pro7-Ang-(1-7), a Mas and MrgD receptor antagonist, prevented the anxiolytic effects induced by this peptide. However, its effects were not altered by the selective Mas receptor antagonist, A779. In conclusion, our data indicates that alamandine, through MrgD, attenuates anxiety-like behavior in male TGR(ASrAOGEN)680, which reinforces the importance of the counter-regulatory RAS axis as promising target for the treatment of neuropsychiatric disorders.
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Angiotensinógeno , Ansiolíticos , Ansiedad , Encéfalo , Ratas Transgénicas , Receptores Acoplados a Proteínas G , Animales , Masculino , Receptores Acoplados a Proteínas G/metabolismo , Receptores Acoplados a Proteínas G/genética , Ratas , Ansiedad/tratamiento farmacológico , Ansiedad/metabolismo , Ansiolíticos/farmacología , Angiotensinógeno/metabolismo , Angiotensinógeno/genética , Encéfalo/metabolismo , Encéfalo/efectos de los fármacos , Receptores de la Hormona Gastrointestinal/metabolismo , Oligopéptidos/farmacología , Proteínas del Tejido NerviosoRESUMEN
BACKGROUND: An unbalance in the renin-angiotensin (Ang) system (RAS) between the Ang II/AT1 and Ang-(1-7)/Mas axis appears to be involved in preeclampsia (PE), in which a reduction in Ang-(1-7) was observed. Here, we tested whether the reduction in the activity of the Ang-(1-7)/Mas axis could be a contributing factor for the development of PE, using Mas-deficient (Mas-/-) mice. METHODS AND RESULTS: Cardiovascular parameters were evaluated by telemetry before, during pregnancy and 4 days postpartum in 20-week-old Mas-/- and wild-type (WT) female mice. Mas-/- mice presented reduced arterial blood pressure (BP) at baseline (91.3 ± 0.8 in Mas-/- vs. 94.0 ± 0.9 mmHg in WT, Diastolic, P<0.05). However, after the 13th day of gestation, BP in Mas-/- mice started to increase, time-dependently, and at day 19 of pregnancy, these animals presented a higher BP in comparison with WT group (90.5 ± 0.7 in Mas-/- vs. 80.3 ± 3.5 mmHg in WT, Diastolic D19, P<0.0001). Moreover, pregnant Mas-/- mice presented fetal growth restriction, increase in urinary protein excretion as compared with nonpregnant Mas-/-, oliguria, increase in cytokines, endothelial dysfunction and reduced ACE, AT1R, ACE2, ET-1A, and eNOS placental mRNA, similar to some of the clinical manifestations found in the development of PE. CONCLUSIONS: These results show that Mas-deletion produces a PE-like state in FVB/N mice.
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Peptidil-Dipeptidasa A , Preeclampsia , Embarazo , Femenino , Ratones , Animales , Humanos , Peptidil-Dipeptidasa A/metabolismo , Proteínas Proto-Oncogénicas/genética , Proteínas Proto-Oncogénicas/metabolismo , Proto-Oncogenes Mas , Preeclampsia/genética , Preeclampsia/metabolismo , Placenta/metabolismo , Sistema Renina-Angiotensina , Receptores Acoplados a Proteínas G/genética , Receptores Acoplados a Proteínas G/metabolismo , Angiotensina II/metabolismo , Fenotipo , Angiotensina I/metabolismo , Fragmentos de Péptidos/metabolismoRESUMEN
GPRC5A is the first member of a new class of orphan receptors coupled to G proteins, which also includes GPRC5B, GPRC5C, and GPRC5D. Since its cloning and identification in the 1990s, substantial progress has been made in understanding the possible functions of this receptor. GPRC5A has been implicated in a variety of cellular events, such as cytoskeleton reorganization, cell proliferation, cell cycle regulation, migration, and survival. It appears to be a central player in different pathological processes, including tumorigenesis, inflammation, immune response, and tissue damage. The levels of GPRC5A expression differ depending on the type of cancer, with increased expression in colon, pancreas, and prostate cancers; decreased expression in lung cancer; and varied results in breast cancer. In this review, we discuss the early discovery of GPRC5A as a phorbol ester-induced gene and later as a retinoic acid-induced gene, its regulation, and its participation in important canonical pathways related to numerous types of tumors and inflammatory processes. GPRC5A represents a potential new target for cancer, inflammation, and immunity therapies.
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Neoplasias Pulmonares , Receptores de Ácido Retinoico , Masculino , Humanos , Ésteres del Forbol , Receptores Acoplados a Proteínas G/genética , Receptores Acoplados a Proteínas G/metabolismo , Neoplasias Pulmonares/patología , Inflamación , TretinoinaRESUMEN
Marfan syndrome (MFS) is an inherited connective tissue disorder. As the spinal growth depends on delicate balance of forces, conditions that affect musculoskeletal matrix often lead to spinal deformities. A large cross-sectional study revealed a 63% prevalence of scoliosis among patients with MFS. Multi-ethnic genome-wide association studies and analyses of human genetic mutations showed that variations and mutations of G protein-coupled receptor 126 (GPR126)locus are associated with multiple skeletal defects, including shorter stature and adolescent idiopathic scoliosis. The study included 54 patients with MFS and 196 control patients. The DNA was extracted from peripheral blood using the saline expulsion method and single nucleotide polymorphism (SNP) determination was carried out using TaqMan probes. Allelic discrimination was performed by RT-qPCR. Significant differences in genotype frequencies were found for SNP rs6570507 in relation to MFS and sex (recessive model, OR 2.46, 95% CI 1.03 -5.87; P = 0.03) and rs7755109 (overdominant model, OR 0.39, 95% CI 0.16-0.91; P = 0.03). The most significant association was found in SNP rs7755109, where the frequency of genotype AG was significantly different between MFS patients with scoliosis and those without (OR 5.68, 95% CI 1.09-29.48; P=0.04). This study, for the first time, examined the genetic association of SNP GPR126 with the risk of scoliosis in patients with connective tissue diseases. The study revealed that SNP rs7755109 is associated with the presence of scoliosis in Mexican patients with MFS.
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Síndrome de Marfan , Escoliosis , Adolescente , Humanos , Síndrome de Marfan/complicaciones , Escoliosis/complicaciones , Estudio de Asociación del Genoma Completo , Estudios Transversales , Receptores Acoplados a Proteínas G/genéticaRESUMEN
When tumoral cell expansion exceeds the vascular supply, regions of hypoxia or low oxygen concentration are generated promoting the formation of new vessels through cell proliferation and migration. Viral G protein-coupled receptor (vGPCR) is associated to Kaposi's sarcoma pathology and induces a paracrine transformation when is stably expressed in murine endothelial cells activating hypoxia-induced transcription factors. Previously, we reported the antiproliferative actions of 1α,25-dihydroxyvitamin D3 (1α,25(OH)2D3) in endothelial cells transformed by the vGPCR (SVEC-vGPCR). Herein, we further investigated if pro-angiogenic factors as AP-1, HIF-1α and VEGF are modulated by 1α,25(OH)2D3. We found by qRT-PCR analysis that the mRNA level of JunB, a negative regulator of cell proliferation, was similarly increased at all-time points tested after 1α,25(OH)2D3 treatment in SVEC-vGPCR cells. Also, mRNA levels of the pro-angiogenic factor c-Fos, which induces tumor invasion, were only decreased during one short period treatment. In addition, Hif-1α mRNA and protein levels were significantly reduced after 1α,25(OH)2D3 treatment in a VDR dependent fashion. However, mRNA levels of the angiogenic activator Vegf, promoted in turn by Hif-1α expression, were surprisingly high depending on VDR expression as well. Moreover, Egr-1, which has been reported to induce VEGF expression independently of HIF-1α, diminished its expression with 1α,25(OH)2D3 treatment, fact that was related to the decline of p-ERK1/2. Altogether, these results suggest a negative modulation of some pro-angiogenic factors like AP-1 and HIF-1α, as part of the antiproliferative mechanism of 1α,25(OH)2D3 in SVEC-vGPCR endothelial cells.
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Células Endoteliales , Herpesvirus Humano 8 , Ratones , Animales , Células Endoteliales/metabolismo , Herpesvirus Humano 8/genética , Herpesvirus Humano 8/metabolismo , Inductores de la Angiogénesis/metabolismo , Factor A de Crecimiento Endotelial Vascular/genética , Factor de Transcripción AP-1/metabolismo , Receptores Acoplados a Proteínas G/genética , Receptores Acoplados a Proteínas G/metabolismo , ARN Mensajero/genética , ARN Mensajero/metabolismo , Hipoxia/metabolismoRESUMEN
Mast cells (MCs) are the main participants in the control of immune reactions associated with inflammation, allergies, defense against pathogens, and tumor growth. Bioactive lipids are lipophilic compounds able to modulate MC activation. Here, we explored some of the effects of the bioactive lipid lysophosphatidylinositol (LPI) on MCs. Utilizing murine bone marrow-derived mast cells (BMMCs), we found that LPI did not cause degranulation, but slightly increased FcεRI-dependent ß-hexosaminidase release. However, LPI induced strong chemotaxis together with changes in LIM kinase (LIMK) and cofilin phosphorylation. LPI also promoted modifications to actin cytoskeleton dynamics that were detected by an increase in cell size and interruptions in the continuity of the cortical actin ring. The chemotaxis and cortical actin ring changes were dependent on GPR55 receptor activation, since the specific agonist O1602 mimicked the effects of LPI and the selective antagonist ML193 prevented them. The LPI and O1602-dependent stimulation of BMMC also led to VEGF, TNF, IL-1α, and IL-1ß mRNA accumulation, but, in contrast with chemotaxis-related processes, the effects on cytokine transcription were dependent on GPR55 and cannabinoid (CB) 2 receptors, since they were sensitive to ML193 and to the specific CB2 receptor antagonist AM630. Remarkably, GPR55-dependent BMMC chemotaxis was observed towards conditioned media from distinct mouse and human cancer cells. Our data suggest that LPI induces the chemotaxis of MCs and leads to cytokine production in MC in vitro with the differential participation of GPR55 and CB2 receptors. These effects could play a significant role in the recruitment of MCs to tumors and the production of MC-derived pro-angiogenic factors in the tumor microenvironment.
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Receptor Cannabinoide CB2 , Receptores Acoplados a Proteínas G , Ratones , Humanos , Animales , Receptores Acoplados a Proteínas G/genética , Receptor Cannabinoide CB2/genética , Quimiotaxis , Mastocitos , Citocinas , Actinas , Receptores de Cannabinoides/genética , Lisofosfolípidos/farmacología , Lisofosfolípidos/fisiologíaRESUMEN
Prokineticin receptor 2 (PROKR2) encodes for a G-protein-coupled receptor that can bind PROK1 and PROK2. Mice lacking Prokr2 have been shown to present abnormal olfactory bulb formation as well as defects in GnRH neuron migration. Patients carrying mutations in PROKR2 typically present hypogonadotropic hypogonadism, anosmia/hyposmia or Kallmann Syndrome. More recently variants in PROKR2 have been linked to several other endocrine disorders. In particular, several patients with pituitary disorders have been reported, ranging from mild phenotypes, such as isolated growth hormone deficiency, to more severe ones, such as septo-optic dysplasia. Here we summarize the changing landscape of PROKR2-related disease, the variants reported to date, and discuss their origin, classification and functional assessment.
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Síndrome de Kallmann , Neuropéptidos , Ratones , Animales , Neuropéptidos/metabolismo , Síndrome de Kallmann/genética , Genotipo , Receptores Acoplados a Proteínas G/genética , Fenotipo , Receptores de Péptidos/genéticaRESUMEN
Genomic resources for Platyhelminthes of the class Monogenea are scarce, despite the diversity of these parasites, some species of which are highly pathogenic to their fish hosts. This work aimed to generate de novo-assembled transcriptomes of two monogenean species, Scutogyrus longicornis (Dactylogyridae) and Rhabdosynochus viridisi (Diplectanidae), providing a protocol for cDNA library preparation with low input samples used in single cell transcriptomics. This allowed us to work with sub-microgram amounts of total RNA with success. These transcriptomes consist of 25,696 and 47,187 putative proteins, respectively, which were further annotated according to the Swiss-Prot, Pfam, GO, KEGG, and COG databases. The completeness values of these transcriptomes evaluated with BUSCO against Metazoa databases were 54.1% and 73%, respectively, which is in the range of other monogenean species. Among the annotations, a large number of terms related to G-protein-coupled receptors (GPCRs) were found. We identified 109 GPCR-like sequences in R. viridisi, and 102 in S. longicornis, including family members specific for Platyhelminthes. Rhodopsin was the largest family according to GRAFS classification. Two putative melatonin receptors found in S. longicornis represent the first record of this group of proteins in parasitic Platyhelminthes. Forty GPCRs of R. viridisi and 32 of S. longicornis that were absent in Vertebrata might be potential drug targets. The present study provides the first publicly available transcriptomes for monogeneans of the subclass Monopisthocotylea, which can serve as useful genomic datasets for functional genomic research of this important group of parasites.
Title: Assemblage de novo du transcriptome et identification des récepteurs couplés aux protéines G (RCPG) chez deux espèces de Monogènes parasites de poissons. Abstract: Les ressources génomiques pour les Plathelminthes de la classe Monogenea sont rares, malgré la diversité de ces parasites dont certaines espèces sont hautement pathogènes pour leurs hôtes poissons. Ce travail visait à générer des transcriptomes assemblés de novo pour deux espèces de monogènes, Scutogyrus longicornis (Dactylogyridae) et Rhabdosynochus viridisi (Diplectanidae), fournissant un protocole pour la préparation de la bibliothèque d'ADNc avec des échantillons à faible apport utilisés en transcriptomique unicellulaire, ce qui a permis de travailler avec des quantités inférieures au microgramme d'ARN total avec succès. Ces transcriptomes se composent de 25 696 et 47 187 protéines putatives, respectivement, qui ont ensuite été annotées selon les bases de données Swiss-Prot, Pfam, GO, KEGG et COG. L'exhaustivité de ces transcriptomes évaluée avec BUSCO par rapport aux bases de données des Métazoaires était respectivement de 54,1 % et 73 %, ce qui est dans la gamme des autres espèces de monogènes. Parmi les annotations, un grand nombre de termes liés aux récepteurs couplés aux protéines G (RCPG) ont été trouvés. Nous avons identifié 109 séquences de type RCPG chez R. viridisi et 102 chez S. longicornis, y compris des membres de la famille spécifiques de Platyhelminthes. La rhodopsine était la plus grande famille selon la classification GRAFS. Deux récepteurs putatifs de la mélatonine trouvés chez S. longicornis représentent le premier signalement de ce groupe de protéines chez les Plathelminthes parasites. Quarante RCPG de R. viridisi et 32 de S. longicornis, qui sont absents chez les Vertébrés, pourraient être des cibles médicamenteuses potentielles. La présente sont fournit les premiers transcriptomes accessibles au public pour les monogènes de la sous-classe Monopisthocotylea, qui peuvent servir d'ensembles de données génomiques utiles pour la recherche génomique fonctionnelle de cet important groupe de parasites.
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Parásitos , Platelmintos , Trematodos , Animales , Transcriptoma , Parásitos/genética , Platelmintos/genética , Trematodos/genética , Receptores Acoplados a Proteínas G/genética , Peces , Proteínas de Unión al GTP/genéticaRESUMEN
G protein-coupled receptors (GPCRs) are plasma membrane proteins associated with an array of functions. Mutations in these receptors lead to a number of genetic diseases, including diseases involving the endocrine system. A particular subset of loss-of-function mutant GPCRs are misfolded receptors unable to traffic to their site of function (i.e. the cell surface plasma membrane). Endocrine disorders in humans caused by GPCR misfolding include, among others, hypo- and hyper-gonadotropic hypogonadism, morbid obesity, familial hypocalciuric hypercalcemia and neonatal severe hyperparathyroidism, X-linked nephrogenic diabetes insipidus, congenital hypothyroidism, and familial glucocorticoid resistance. Several in vitro and in vivo experimental approaches have been employed to restore function of some misfolded GPCRs linked to endocrine disfunction. The most promising approach is by employing pharmacological chaperones or pharmacoperones, which assist abnormally and incompletely folded proteins to refold correctly and adopt a more stable configuration to pass the scrutiny of the cell's quality control system, thereby correcting misrouting. This review covers the most important aspects that regulate folding and traffic of newly synthesized proteins, as well as the experimental approaches targeted to overcome protein misfolding, with special focus on GPCRs involved in endocrine diseases.
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Enfermedades del Sistema Endocrino , Pliegue de Proteína , Membrana Celular/metabolismo , Enfermedades del Sistema Endocrino/metabolismo , Enfermedades del Sistema Endocrino/terapia , Humanos , Recién Nacido , Mutación , Receptores Acoplados a Proteínas G/genética , Receptores Acoplados a Proteínas G/metabolismoRESUMEN
Attention deficit/hyperactivity disorder (ADHD) is the most common childhood neurodevelopmental disorder. Single nucleotide polymorphisms (SNPs) in the Adhesion G Protein-Coupled Receptor L3 (ADGRL3) gene are associated with increased susceptibility to developing ADHD worldwide. However, the effect of ADGRL3 non-synonymous SNPs (nsSNPs) on the ADGRL3 protein function is vastly unknown. Using several bioinformatics tools to evaluate the impact of mutations, we found that nsSNPs rs35106420, rs61747658, and rs734644, previously reported to be associated and in linkage with ADHD in disparate populations from the world over, are predicted as pathogenic variants. Docking analysis of rs35106420, harbored in the ADGLR3-hormone receptor domain (HRM, a common extracellular domain of the secretin-like GPCRs family), showed that HRM interacts with the Glucose-dependent insulinotropic polypeptide (GIP), part of the incretin hormones family. GIP has been linked to the pathogenesis of diabetes mellitus, and our analyses suggest a potential link to ADHD. Overall, the comprehensive application of bioinformatics tools showed that functional mutations in the ADGLR3 gene disrupt the standard and wild ADGRL3 structure, most likely affecting its metabolic regulation. Further in vitro experiments are granted to evaluate these in silico predictions of the ADGRL3-GIP interaction and dissect the complexity underlying the development of ADHD.
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Trastorno por Déficit de Atención con Hiperactividad , Receptores Acoplados a Proteínas G , Trastorno por Déficit de Atención con Hiperactividad/genética , Niño , Polipéptido Inhibidor Gástrico/genética , Polipéptido Inhibidor Gástrico/metabolismo , Genómica , Glucosa , Humanos , Incretinas/genética , Incretinas/metabolismo , Neurogénesis , Receptores Acoplados a Proteínas G/genética , Receptores de Péptidos , SecretinaRESUMEN
Alterations of circulating and placental levels of kisspeptin have been associated with gestational diseases. However, there are still no studies on the placental and decidual expression of Kiss1 and its receptor Kiss1r in maternal hypothyroidism, which is the aim of this work. We demonstrate that the fetoplacental restriction caused by hypothyroidism in rats is associated with a reduction in the Kiss1r expression and reduced Kiss1 and Kiss1r mRNA levels in the decidua and/or placenta. This demonstrate that fetoplacental restriction in hypothyroid rats is linked with a suppression of the kisspeptin/Kiss1r system at the maternal-fetal interface.
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Hipotiroidismo , Kisspeptinas , Animales , Femenino , Kisspeptinas/genética , Kisspeptinas/metabolismo , Placenta/metabolismo , Embarazo , Ratas , Receptores Acoplados a Proteínas G/genética , Receptores Acoplados a Proteínas G/metabolismo , Receptores de Kisspeptina-1/genética , Receptores de Kisspeptina-1/metabolismoRESUMEN
OBJECTIVE: To investigate whether single nucleotide polymorphisms (SNPs) in the ADGRL3, DRD4, and SNAP25 genes are associated with and predict ADHD severity in families from a Caribbean community. METHOD: ADHD severity was derived using latent class cluster analysis of DSM-IV symptomatology. Family-based association tests were conducted to detect associations between SNPs and ADHD severity latent phenotypes. Machine learning algorithms were used to build predictive models of ADHD severity based on demographic and genetic data. RESULTS: Individuals with ADHD exhibited two seemingly independent latent class severity configurations. SNPs harbored in DRD4, SNAP25, and ADGRL3 showed evidence of linkage and association to symptoms severity and a potential pleiotropic effect on distinct domains of ADHD severity. Predictive models discriminate severe from non-severe ADHD in specific symptom domains. CONCLUSION: This study supports the role of DRD4, SNAP25, and ADGRL3 genes in outlining ADHD severity, and a new prediction framework with potential clinical use.
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Trastorno por Déficit de Atención con Hiperactividad , Receptores Acoplados a Proteínas G/genética , Receptores de Péptidos/genética , Trastorno por Déficit de Atención con Hiperactividad/diagnóstico , Trastorno por Déficit de Atención con Hiperactividad/genética , Manual Diagnóstico y Estadístico de los Trastornos Mentales , Humanos , Aprendizaje Automático , Fenotipo , Polimorfismo de Nucleótido Simple/genética , Receptores de Dopamina D4/genética , Proteína 25 Asociada a Sinaptosomas/genéticaRESUMEN
Misfolding of G protein-coupled receptors (GPCRs) caused by mutations frequently leads to disease due to intracellular trapping of the conformationally abnormal receptor. Several endocrine diseases due to inactivating mutations in GPCRs have been described, including X-linked nephrogenic diabetes insipidus, thyroid disorders, familial hypocalciuric hypercalcemia, obesity, familial glucocorticoid deficiency [melanocortin-2 receptor, MC2R (also known as adrenocorticotropin receptor, ACTHR), and reproductive disorders. In these mutant receptors, misfolding leads to endoplasmic reticulum retention, increased intracellular degradation, and deficient trafficking of the abnormal receptor to the cell surface plasma membrane, causing inability of the receptor to interact with agonists and trigger intracellular signaling. In this review, we discuss the mechanisms whereby mutations in GPCRs involved in endocrine function in humans lead to misfolding, decreased plasma membrane expression of the receptor protein, and loss-of-function diseases, and also describe several experimental approaches employed to rescue trafficking and function of the misfolded receptors. Special attention is given to misfolded GPCRs that regulate reproductive function, given the key role played by these particular membrane receptors in sexual development and fertility, and recent reports on promising therapeutic interventions targeting trafficking of these defective proteins to rescue completely or partially their normal function.
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Enfermedades del Sistema Endocrino/genética , Enfermedades del Sistema Endocrino/metabolismo , Mutación , Receptores Acoplados a Proteínas G/química , Receptores Acoplados a Proteínas G/genética , Animales , Membrana Celular/metabolismo , Retículo Endoplásmico/metabolismo , Humanos , Pliegue de Proteína , Transporte de Proteínas , Receptores Acoplados a Proteínas G/metabolismo , Receptores de Gonadotropina/metabolismo , Transducción de Señal/genéticaRESUMEN
Papillary thyroid cancer (PTC), whose incidence has been increasing in the last years, occurs more frequently in women. Experimental studies suggested that estrogen could be an important risk factor for the higher female incidence. In fact, it has been demonstrated that 17ß-estradiol (E2) could increase proliferation and dedifferentiation in thyroid follicular cells. Genomic estrogen responses are typically mediated through classical estrogen receptors, the α and ß isoforms, which have been described in normal and abnormal human thyroid tissue. Nevertheless, effects mediated through G protein estrogen receptor 1 (GPR30/GPER/GPER1), described in some thyroid cancer cell lines, could be partially responsible for the regulation of growth in normal cells. In this study, GPER1 gene and protein expression are described in non-malignant and in papillary thyroid cancer (PTC), as well as its association with clinical features of patients with PTC. The GPER1 expression was lower in PTC as compared to paired non-malignant thyroid tissues in fresh samples of PTC and in silico analysis of GEO and TCGA databases. In PTC cases of TCGA database, low GPER1 mRNA expression was independently associated with metastatic lymph nodes, female gender, and BRAF mutation. Besides, GPER1 mRNA levels were positively correlated with mRNA levels of thyroid differentiation genes. These results support the hypothesis that GPER1 have a role in PTC tumorigenesis and might be a potential target for its therapy. Further studies are needed to determine the functionality of these receptors in normal and diseased thyroid.
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Biología Computacional/métodos , Regulación hacia Abajo , Receptores de Estrógenos/genética , Receptores Acoplados a Proteínas G/genética , Cáncer Papilar Tiroideo/genética , Neoplasias de la Tiroides/genética , Estudios de Casos y Controles , Bases de Datos Genéticas , Femenino , Perfilación de la Expresión Génica , Regulación Neoplásica de la Expresión Génica , Humanos , Metástasis Linfática , Masculino , Mutación , Proteínas Proto-Oncogénicas B-raf/genética , Caracteres SexualesRESUMEN
Cutaneous mast cells (MCs) express Mas-related G protein-coupled receptor-X2 (MRGPRX2; mouse ortholog MrgprB2), which is activated by an ever-increasing number of cationic ligands. Antimicrobial host defense peptides (HDPs) generated by keratinocytes contribute to host defense likely by 2 mechanisms, one involving direct killing of microbes and the other via MC activation through MRGPRX2. However, its inappropriate activation may cause pseudoallergy and likely contribute to the pathogenesis of rosacea, atopic dermatitis, allergic contact dermatitis, urticaria, and mastocytosis. Gain- and loss-of-function missense single nucleotide polymorphisms in MRGPRX2 have been identified. The ability of certain ligands to serve as balanced or G protein-biased agonists has been defined. Small-molecule HDP mimetics that display both direct antimicrobial activity and activate MCs via MRGPRX2 have been developed. In addition, antibodies and reagents that modulate MRGPRX2 expression and signaling have been generated. In this article, we provide a comprehensive update on MrgprB2 and MRGPRX2 biology. We propose that harnessing MRGPRX2's host defense function by small-molecule HDP mimetics may provide a novel approach for the treatment of antibiotic-resistant cutaneous infections. In contrast, MRGPRX2-specific antibodies and inhibitors could be used for the modulation of allergic and inflammatory diseases that are mediated via this receptor.
Asunto(s)
Mastocitos/inmunología , Mutación Missense , Proteínas del Tejido Nervioso/inmunología , Polimorfismo de Nucleótido Simple , Receptores Acoplados a Proteínas G/inmunología , Receptores de Neuropéptido/inmunología , Enfermedades de la Piel , Piel/inmunología , Animales , Antiinfecciosos/uso terapéutico , Materiales Biomiméticos/uso terapéutico , Humanos , Mastocitos/patología , Ratones , Proteínas del Tejido Nervioso/genética , Receptores Acoplados a Proteínas G/genética , Receptores de Neuropéptido/genética , Transducción de Señal/efectos de los fármacos , Transducción de Señal/genética , Transducción de Señal/inmunología , Piel/patología , Enfermedades de la Piel/tratamiento farmacológico , Enfermedades de la Piel/genética , Enfermedades de la Piel/inmunología , Enfermedades de la Piel/patologíaRESUMEN
Leucine-rich repeats containing G protein-coupled receptor 4 (LGR4) is a receptor that belongs to the superfamily of G protein-coupled receptors that can be activated by R-spondins (RSPOs), Norrin, circLGR4, and the ligand of the receptor activator of nuclear factor kappa-B (RANKL) ligands to regulate signaling pathways in normal and pathological processes. LGR4 is widely expressed in different tissues where it has multiple functions such as tissue development and maintenance. LGR4 mainly acts through the Wnt/ß-catenin pathway to regulate proliferation, survival, and differentiation. In cancer, LGR4 participates in tumor progression, invasion, and metastasis. Furthermore, recent evidence reveals that LGR4 is essential for the regulation of the cancer stem cell population by controlling self-renewal and regulating stem cell properties. This review summarizes the function of LGR4 and its ligands in normal and malignant processes.
Asunto(s)
Neoplasias/metabolismo , Receptores Acoplados a Proteínas G/metabolismo , Animales , Carcinogénesis , Femenino , Humanos , Ligandos , Masculino , Ratones , MicroARNs/genética , Modelos Biológicos , Neoplasias/etiología , Neoplasias/patología , Células Madre Neoplásicas/metabolismo , Células Madre Neoplásicas/patología , Receptores Acoplados a Proteínas G/química , Receptores Acoplados a Proteínas G/genética , Distribución Tisular , Vía de Señalización WntRESUMEN
Estrogen receptors (ER) mediate functions beyond their endocrine roles, as modulation of cardiovascular, renal, and immune systems through anti-inflammatory and anti-apoptotic effects, preventing necrosis of cardiomyocytes and endothelial cells, and attenuating cardiac hypertrophy. Estradiol (E2) prevents cardiac dysfunction, increases nitric oxide synthesis, and reduces the proliferation of vascular cells, yielding protective effects, regardless of gender. Such actions are mediated by ER (ER-alpha (ERα), ER-beta (ERß), or G protein-coupled ER (GPER)) through genomic or non-genomic pathways, which regulate cardiovascular function and prevent tissue remodeling. Despite the extensive knowledge on the cardioprotective effects of estrogen, clinical studies conducted on myocardial infarction (MI) and cardiovascular diseases still include favorable and unfavorable profiles. The purpose of this review is to provide up-to-date information regarding molecular, preclinical, and clinical aspects of cardiovascular E2 effects and ER modulation as a potential therapeutic target for the treatment of MI-induced cardiac dysfunction.