The development of the human uterus: morphogenesis to menarche

2020 ◽  
Vol 27 (1) ◽  
pp. 1-26
Author(s):  
Marwan Habiba ◽  
Rosemarie Heyn ◽  
Paola Bianchi ◽  
Ivo Brosens ◽  
Giuseppe Benagiano
Keyword(s):  
Molecular Mechanisms ◽  
Uterine Bleeding ◽  
Molecular Techniques ◽  
Receptor Expression ◽  
Abnormal Development ◽  
Uterine Disease ◽  
Adult Onset ◽  
Uterine Anomalies ◽  
Mullerian Ducts ◽  
Uterine Development

ABSTRACT There is emerging evidence that early uterine development in humans is an important determinant of conditions such as ontogenetic progesterone resistance, menstrual preconditioning, defective deep placentation and pre-eclampsia in young adolescents. A key observation is the relative infrequency of neonatal uterine bleeding and hormone withdrawal at birth. The origin of the uterus from the fusion of the two paramesonephric, or Müllerian, ducts was described almost 200 years ago. The uterus forms around the 10th week of foetal life. The uterine corpus and the cervix react differently to the circulating steroid hormones during pregnancy. Adult uterine proportions are not attained until after puberty. It is unclear if the endometrial microbiome and immune response—which are areas of growing interest in the adult—play a role in the early stages of uterine development. The aim is to review the phases of uterine development up until the onset of puberty in order to trace the origin of abnormal development and to assess current knowledge for features that may be linked to conditions encountered later in life. The narrative review incorporates literature searches of Medline, PubMed and Scopus using the broad terms individually and then in combination: uterus, development, anatomy, microscopy, embryology, foetus, (pre)-puberty, menarche, microbiome and immune cells. Identified articles were assessed manually for relevance, any linked articles and historical textbooks. We included some animal studies of molecular mechanisms. There are competing theories about the contributions of the Müllerian and Wolffian ducts to the developing uterus. Endometrium features are suggestive of an oestrogen effect at 16–20 weeks gestation. The discrepancy in the reported expression of oestrogen receptor is likely to be related to the higher sensitivity of more recent techniques. Primitive endometrial glands appear around 20 weeks. Features of progestogen action are expressed late in the third trimester. Interestingly, progesterone receptor expression is higher at mid-gestation than at birth when features of endometrial maturation are rare. Neonatal uterine bleeding occurs in around 5% of neonates. Myometrial differentiation progresses from the mesenchyme surrounding the endometrium at the level of the cervix. During infancy, the uterus and endometrium remain inactive. The beginning of uterine growth precedes the onset of puberty and continues for several years after menarche. Uterine anomalies may result from fusion defects or atresia of one or both Müllerian ducts. Organogenetic differentiation of Müllerian epithelium to form the endometrial and endocervical epithelium may be independent of circulating steroids. A number of genes have been identified that are involved in endometrial and myometrial differentiation although gene mutations have not been demonstrated to be common in cases of uterine malformation. The role, if any, of the microbiome in relation to uterine development remains speculative. Modern molecular techniques applied to rodent models have enhanced our understanding of uterine molecular mechanisms and their interactions. However, little is known about functional correlates or features with relevance to adult onset of uterine disease in humans. Prepubertal growth and development lends itself to non-invasive diagnostics such as ultrasound and MRI. Increased awareness of the occurrence of neonatal uterine bleeding and of the potential impact on adult onset disease may stimulate renewed research in this area.

scholarly journals Unicornuate Uterus with Rudimentary Horn as a Rare Etiology of Secondary Dysmenorrhea: A Case Report

2021 ◽  
pp. 1-4
Author(s):  
Zuhdi Khalid Nagshabandi ◽  
Bindu Isaac ◽  
Inshia Begum
Keyword(s):  
Uterine Cavity ◽  
Abnormal Development ◽  
Rudimentary Horn ◽  
Unicornuate Uterus ◽  
Appropriate Treatment ◽  
Pelvic Ultrasonography ◽  
Uterine Anomalies ◽  
Uterine Anomaly ◽  
Mullerian Ducts ◽  
Secondary Dysmenorrhea

Congenital uterine anomalies are an uncommon type of female genital malformations caused by abnormal development of müllerian ducts during embryogenesis. Patients with an obstructive uterine anomaly have a higher risk of developing gynecological and obstetric complications that may present at menarche or later in life. We present a case of severe dysmenorrhea in a young teenager caused by obstructive hematometra in a noncommunicating horn of the unicornuate uterus. A differential diagnosis of a possible anomaly was made using 2-dimensional pelvic ultrasonography, which was later confirmed using MRI that revealed an anomalous uterine cavity with a single left-sided cornua communicating with the cervix and a distended right-sided rudimentary horn. She underwent a right salpingectomy with rudimentary horn excision, which was successfully managed laparoscopically. This case emphasizes the importance of physicians being cognizant in identifying patients with uterine anomaly to provide appropriate treatment and prevent adverse reproductive outcomes.

Association of antimullerian hormone with the size of the appendix testis, the androgen and estrogen receptors and their expression in the appendix testis, in congenital cryptorchidism

2021 ◽  
Vol 0 (0) ◽  
Author(s):  
Xenophon Sinopidis ◽  
Eirini Kostopoulou ◽  
Andrea Paola Rojas-Gil ◽  
Antonios Panagidis ◽  
Eleni Kourea ◽  
...  
Keyword(s):  
Estrogen Receptor ◽  
Receptor Expression ◽  
Testicular Descent ◽  
Antimullerian Hormone ◽  
Mullerian Ducts ◽  
Score Method ◽  
Antimüllerian Hormone ◽  
Unilateral Cryptorchidism ◽  
Appendix Testis

Abstract Objectives Antimullerian hormone (AMH) causes regression of the mullerian ducts in the male fetus. The appendix testis (AT) is a vestigial remnant of mullerian duct origin, containing both androgen (AR) and estrogen (ER) receptors. The role of both AMH and AT in testicular descent is yet to be studied. We investigated the possible association of AMH with AT size, the AR and ER, and their expression in the AT, in congenital cryptorchidism. Methods A total of 26 patients with congenital unilateral cryptorchidism and 26 controls with orthotopic testes were investigated, and 21 ATs were identified in each group. AMH and insulin-like three hormone (INSL3) concentrations were measured with spectrophotometry. AR and ER receptor expression was assessed with immunohistochemistry using monoclonal antibodies R441 for AR and MAB463 for ER. For the estimation of receptor expression, the Allred Score method was used. Results AMH concentrations did not present significant differences between patients with congenital cryptorchidism and the controls. Also, no correlation was found between AMH, INSL3, and AT length. Allred scores did not present significant differences. However, expression percentiles and intensity for both receptors presented significant differences. Three children with cryptorchidism and the highest AMH levels also had the highest estrogen receptor scores in the AT. Conclusions No association was found between AMH and the studied major parameters. However, higher AMH concentrations, in combination with higher estrogen receptor scores in the AT, may play a role in cryptorchidism in some children. Larger population samples are needed to verify this observation.

scholarly journals COXIBs and 2,5-dimethylcelecoxib counteract the hyperactivated Wnt/β-catenin pathway and COX-2/PGE2/EP4 signaling in glioblastoma cells

BMC Cancer ◽  
2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Aleksandra Majchrzak-Celińska ◽  
Julia O. Misiorek ◽  
Nastassia Kruhlenia ◽  
Lukasz Przybyl ◽  
Robert Kleszcz ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Cell Viability ◽  
Methylation Level ◽  
Molecular Mechanisms ◽  
Methylation Status ◽  
Receptor Expression ◽  
Cell Cycle Distribution ◽  
Ep4 Receptor ◽  
Cox 2 ◽  
The Impact

Abstract Background Glioblastoma (GBM) is the deadliest and the most common primary brain tumor in adults. The invasiveness and proliferation of GBM cells can be decreased through the inhibition of Wnt/β-catenin pathway. In this regard, celecoxib is a promising agent, but other COXIBs and 2,5-dimethylcelecoxib (2,5-DMC) await elucidation. Thus, the aim of this study was to analyze the impact of celecoxib, 2,5-DMC, etori-, rofe-, and valdecoxib on GBM cell viability and the activity of Wnt/β-catenin pathway. In addition, the combination of the compounds with temozolomide (TMZ) was also evaluated. Cell cycle distribution and apoptosis, MGMT methylation level, COX-2 and PGE2 EP4 protein levels were also determined in order to better understand the molecular mechanisms exerted by these compounds and to find out which of them can serve best in GBM therapy. Methods Celecoxib, 2,5-DMC, etori-, rofe- and valdecoxib were evaluated using three commercially available and two patient-derived GBM cell lines. Cell viability was analyzed using MTT assay, whereas alterations in MGMT methylation level were determined using MS-HRM method. The impact of COXIBs, in the presence and absence of TMZ, on Wnt pathway was measured on the basis of the expression of β-catenin target genes. Cell cycle distribution and apoptosis analysis were performed using flow cytometry. COX-2 and PGE2 EP4 receptor expression were evaluated using Western blot analysis. Results Wnt/β-catenin pathway was attenuated by COXIBs and 2,5-DMC irrespective of the COX-2 expression profile of the treated cells, their MGMT methylation status, or radio/chemoresistance. Celecoxib and 2,5-DMC were the most cytotoxic. Cell cycle distribution was altered, and apoptosis was induced after the treatment with celecoxib, 2,5-DMC, etori- and valdecoxib in T98G cell line. COXIBs and 2,5-DMC did not influence MGMT methylation status, but inhibited COX-2/PGE2/EP4 pathway. Conclusions Not only celecoxib, but also 2,5-DMC, etori-, rofe- and valdecoxib should be further investigated as potential good anti-GBM therapeutics.

P–540 A feasible diagnostic approach for the cryptic subtelomeric traslocations in early recurrent miscarriage patients by preimplantation genetic testing (PGT)

2021 ◽  
Vol 36 (Supplement_1) ◽  
Author(s):  
B Lledo ◽  
R Morales ◽  
J A Ortiz ◽  
A Cascales ◽  
A Fabregat ◽  
...  
Keyword(s):  
Genetic Testing ◽  
Recurrent Miscarriage ◽  
Chromosome Translocation ◽  
Accurate Diagnosis ◽  
Molecular Techniques ◽  
Telomeric Region ◽  
Whole Genome ◽  
Preimplantation Genetic Testing ◽  
Uterine Anomalies ◽  
Cryptic Translocation

Abstract Study question Could cryptic subtelomeric traslocations in early recurrent miscarriage patients be diagnosed by preimplantation genetic testing? Summary answer PGT is a powerful tool to detect subtelomeric cryptic traslocations identifying the cause of early recurrent miscarriage and allowing subsequent genetic counselling. What is known already: Chromosome translocations are frequently associated with birth defects, spontaneous early pregnancy losses and infertility. However, submicroscopic traslocations (so-called cryptic traslocations) are too small to be detected by conventional karyotyping.. Due to balanced status, high resolution molecular techniques as arrayCGH are not able to detect it. Thus, cryptic traslocations detection is challenging. PGT is able to detect CNVs at higher resolution than routine karyotyping. Therefore, the recurrent diagnosis of CNV at embryo level could suggest a subchromosomal parental traslocation. The aim of this study is to investigate the feasibility of using PGT as an indicator of parental balanced cryptic traslocations. Study design, size, duration We included three couples who underwent PGT for unexplained repeated pregnancy loss (RPL) in our clinic from February 2020 to November 2020. Common established causes of RPL (uterine anomalies, antiphospholipid syndrome, immunological, hormonal and metabolic disorders) were previously rouled-out. Even couple karyotypes were normal. Twenty-three embryos from those couples were biopsied at blastocyst and analysed for CNVs detection using low coverage whole genome NGS. Participants/materials, setting, methods PGT by NGS was performed by Veriseq-NGS (Illumina), with previous whole genome amplification. Fluorescence in situ hybridization (FISH) using parental blood samples were performed to validate the origin of subchromosomal number variation. Commercially available subtelomeric specific probes were selected according to the CNV identified and the procedures were performed according to the manufacturer’s protocols. Main results and the role of chance Overall, CNVs of terminal duplication and deletion that imply unbalanced traslocation derivatives were detected in the 43.5% of biopsied embryos. For couple 1, 4 out of 5 embryos (80%) carried deletion of telomeric region on chromosomes 5 and 21. Three out of 6 biopsed embyos (50%) were diagnosed with subchromosomal copy variants at telomeric region on chromosomes 6 and 16 for couple 2. In the case of couple 3, three out of 12 embryos (25%) were carriers of CNV at subtelomeric region on chromosomes 2 and 6. The size of CNVs detected ranges from 8Mb to 20Mb. Accurate diagnosis with the parental study was made by FISH. The combination of probes to detect the structural chromosome alteration were: Tel5qter-LSI21q, Tel6pter-CEP16 and Tel6pter-CEP6 for each couple respectively. The FISH studies reveal that CNVs were inherited from one parent carrying the balanced cryptic traslocation. Ultimately, the abnormal karyotype from the carrier parent were 46,XY,t(5;21)(q33.2;q21.2) for couple 1, 46,XY,t(6;16)(p22.3;q22.1) for couple 2 and 46,XY,t(2;6)(p25.1;p24.2) for couple 3. Finally, each couple performed a cryotransfer of a single normal balanced embryo. Two pregnancies are ongoing. Limitations, reasons for caution The main limitation of this approach is the NGS- PGT resolution. CNVs smaller than 5Mb could not be detected. Wider implications of the findings: This study shows the value of PGT for unexplained RPL, followed by parental FISH to better characterize CNVs and identify couples in whom one partner carries a cryptic translocation. Accurate diagnosis of parental chromosome translocation can achieve with FISH only, but FISH would not be performed unless PGT showed CNVs. Trial registration number Not applicable

scholarly journals Exogenous Promoter Triggers APETALA3 Silencing through RNA-Directed DNA Methylation Pathway in Arabidopsis

2019 ◽  
Vol 20 (18) ◽  
pp. 4478 ◽  
Author(s):  
Benqi Wang ◽  
Jie Liu ◽  
Lei Chu ◽  
Xue Jing ◽  
Huadong Wang ◽  
...  
Keyword(s):  
Transgenic Plants ◽  
Molecular Mechanisms ◽  
Plant Reproduction ◽  
Vital Role ◽  
Abnormal Development ◽  
Class A ◽  
Methylation Pathway ◽  
Class B ◽  
Transgenic Lines ◽  
Morphological Defects

The development of floral organs plays a vital role in plant reproduction. In our research, the APETALA3 (AP3) promoter-transgenic lines showed abnormal developmental phenotypes in stamens and petals. The aim of this study is to understand the molecular mechanisms of the morphological defects in transgenic plants. By performing transgenic analysis, it was found that the AP3-promoted genes and the vector had no relation to the morphological defects. Then, we performed the expression analysis of the class A, B, and C genes. A dramatic reduction of transcript levels of class B genes (AP3 and PISTILLATA) was observed. Additionally, we also analyzed the methylation of the promoters of class B genes and found that the promoter of AP3 was hypermethylated. Furthermore, combining mutations in rdr2-2, drm1/2, and nrpd1b-11 with the AP3-silencing lines rescued the abnormal development of stamens and petals. The expression of AP3 was reactivated and the methylation level of AP3 promoter was also reduced in RdDM-defective AP3-silencing lines. Our results showed that the RdDM pathway contributed to the transcriptional silencing in the transgenic AP3-silencing lines. Moreover, the results revealed that fact that the exogenous fragment of a promoter could trigger the methylation of homologous endogenous sequences, which may be ubiquitous in transgenic plants.

Protective and Destructive Immunity in the Periodontium: Part 2—T-cell-mediated Immunity in the Periodontium

2006 ◽  
Vol 85 (3) ◽  
pp. 209-219 ◽  
Author(s):  
Y.-T.A. Teng
Keyword(s):  
T Cell ◽  
Porphyromonas Gingivalis ◽  
Virulence Factors ◽  
Molecular Mechanisms ◽  
Molecular Techniques ◽  
Actinobacillus Actinomycetemcomitans ◽  
Antigenic Determinants ◽  
Cell Mediated Immunity ◽  
Receptor Activator ◽  
Molecular Patterns

Based on the results of recent research in the field and Part 1 of this article (in this issue), the present paper will discuss the protective and destructive aspects of the T-cell-mediated adaptive immunity associated with the bacterial virulent factors or antigenic determinants during periodontal pathogenesis. Attention will be focused on: (i) osteoimmunology and periodontal disease; (ii) some molecular techniques developed and applied to identify critical microbial virulence factors or antigens associated with host immunity (with Actinobacillus actinomycetemcomitans and Porphyromonas gingivalis as the model species); and (iii) summarizing the identified virulence factors/antigens associated with periodontal immunity. Thus, further understanding of the molecular mechanisms of the host’s T-cell-mediated immune responses and the critical microbial antigens related to disease pathogenesis will facilitate the development of novel therapeutics or protocols for future periodontal treatments. Abbreviations used in the paper are as follows: A. actinomycetemcomitans ( Aa), Actinobacillus actinomycetemcomitans; Ab, antibody; DC, dendritic cells; mAb, monoclonal antibody; pAb, polyclonal antibody; OC, osteoclast; PAMP, pathogen-associated molecular patterns; P. gingivalis ( Pg), Porphyromonas gingivalis; RANK, receptor activator of NF-κB; RANKL, receptor activator of NF-κB ligand; OPG, osteoprotegerin; TCR, T-cell-receptors; TLR, Toll-like receptors.

FC 006PP2A PHOSPHATASE INHIBITION IS ANTI-FIBROTIC THROUGH SER77 PHOSPHORYLATION-MEDIATED ARNT/ARNT HOMODIMER FORMATION

2021 ◽  
Vol 36 (Supplement_1) ◽  
Author(s):  
Gunsmaa Nyamsuren ◽  
Gregor Christof Rapp ◽  
Björn Tampe ◽  
Michael Zeisberg
Keyword(s):  
Molecular Mechanisms ◽  
Therapeutic Potential ◽  
Critical Role ◽  
Phosphorylation Site ◽  
Receptor Expression ◽  
Proximity Ligation Assay ◽  
Proximity Ligation ◽  
Aryl Hydrocarbon ◽  
Ureter Obstruction

Abstract Background and Aims Aryl hydrocarbon receptor nuclear translocator (ARNT) mediates anti-fibrotic activity in kidney and liver through induction of ALK3-receptor expression and subsequently increased Smad1/5/8 signaling. While expression of ARNT can be pharmacologically induced by sub-immunosuppressive doses of FK506 or by GPI1046, its anti-fibrotic activity is only realized when ARNT-ARNT homodimers form, as opposed to formation of ARNT-AHR or ARNT-HIF1α heterodimers. Mechanisms underlying ARNTs dimerization decision to specifically form ARNT-ARNT homodimers and possible cues to specifically induce ARNT homodimerization have been previously unknown. We here aimed to elucidate the molecular mechanisms underlying control of ARNT dimerization decision and to explore its therapeutic potential. Method We analyzed dimerization of recombinant and native ARNT by immunoprecipitation, MALDI-TOF mass spectrometry, and LS-MS/MS analysis and proximity ligation assay. Phosphorylation sites were mapped through generation of phosphorylation site mutants and through pharmacological inhibition. For in vivo analysis we challenged mice with model of unilateral ureter obstruction and carbon tetrachloride to induce fibrosis in kidney and liver. Results Here we report that inhibition of PP2A phosphatase activity increases intracellular accumulation of ARNT-ARNT homodimers. This effect is dependent on enhanced ARNT-ARNT homodimerization and decreased ARNT proteolytic degradation, but independent of ARNT transcription (which remains unchanged upon PP2A inhibition). We further identify that Ser77 phosphorylation plays a critical role in ARNT homodimerization, as ARNT-ARNT homodimers do not form with Ser77/Asp-mutant ARNT proteins. In light of previous studies which identified anti-fibrotic activity upon increased ARNT expression, we further demonstrate attenuated fibrosis upon monotherapy with the PP2A inhibitor LB100, and additive anti-fibrotic activities upon combination with pharmacological inducers of ARNT expression FK506 or GPI1046 in murine models of kidney and liver fibrosis. Conclusion Our study provides additional evidence for the anti-fibrotic activity of ARNT and reveals Ser77 phosphorylation as a novel pharmacological target to realize the therapeutic potential of increased ARNT transactivation activity.

scholarly journals BDNF-induced local translation of GluA1 is regulated by HNRNP A2/B1

2020 ◽  
Vol 6 (47) ◽  
pp. eabd2163
Author(s):  
Youngseob Jung ◽  
Ji-Young Seo ◽  
Hye Guk Ryu ◽  
Do-Yeon Kim ◽  
Kyung-Ha Lee ◽  
...  
Keyword(s):  
Ampa Receptor ◽  
Molecular Mechanisms ◽  
Receptor Expression ◽  
Spine Density ◽  
Entry Site ◽  
Independent Manner ◽  
Internal Ribosome Entry ◽  
Ampa Receptor Subunit ◽  
Internal Initiation ◽  
Underlying Mechanisms

The AMPA receptor subunit GluA1 is essential for induction of synaptic plasticity. While various regulatory mechanisms of AMPA receptor expression have been identified, the underlying mechanisms of GluA1 protein synthesis are not fully understood. In neurons, axonal and dendritic mRNAs have been reported to be translated in a cap-independent manner. However, molecular mechanisms of cap-independent translation of synaptic mRNAs remain largely unknown. Here, we show that GluA1 mRNA contains an internal ribosome entry site (IRES) in the 5′UTR. We also demonstrate that heterogeneous nuclear ribonucleoprotein (hnRNP) A2/B1 interacts with GluA1 mRNA and mediates internal initiation of GluA1. Brain-derived neurotrophic factor (BDNF) stimulation increases IRES-mediated GluA1 translation via up-regulation of HNRNP A2/B1. Moreover, BDNF-induced GluA1 expression and dendritic spine density were significantly decreased in neurons lacking hnRNP A2/B1. Together, our data demonstrate that IRES-mediated translation of GluA1 mRNA is a previously unidentified feature of local expression of the AMPA receptor.

Gene Trap, Gene Knockout, Gene Knock-In, and Transgenics in Vascular Development

1999 ◽  
Vol 82 (08) ◽  
pp. 865-869 ◽  
Author(s):  
Thomas Sato
Keyword(s):  
Animal Models ◽  
Molecular Mechanisms ◽  
Vascular System ◽  
System Development ◽  
Gene Knockout ◽  
Vascular Development ◽  
Branching Morphogenesis ◽  
Abnormal Development ◽  
Organ Systems ◽  
Almost All

IntroductionThe vascular system is one of the first organ systems to develop in our bodies. Normal development and maturation of the physiological functions of almost all of the other organs are critically dependent on the accurate and tightly controlled establishment of the vascular system. Our understanding of the mechanisms underlying the formation of the vascular system during development is still in its infancy. With further understanding of these mechanisms, we may eventually be able to correct the abnormal development and the malfunctioning of many organs by therapeutically modulating the morphology and/or physiological function of the vascular system.Our further understanding of the vascular development can, in part, be achieved by discovering the molecules that play critical roles in this process. We could also achieve this goal by learning more about the functions of previously identified molecules in the vascular system. Discovery of new processes underlying the development of the vascular system will also contribute to further understanding of these molecular mechanisms.Recent advances, using the whole genome approach, have resulted in a flood of new information. This trend will continue, and fortunately, a number of molecular reagents will become available. Therefore, the field will likely experience an exponential growth in terms of novel biological insights and discovering the mechanisms of vascular system development.Occasionally, reductionistic approaches help to systematically address a number of biological problems, including the problems associated with vascular system development. One such approach is to choose an organism that allows us to systematically address these biological questions. The choice of animal models that are well-suited for the study of a particular question has led to a large number of discoveries. To address questions in vascular system development, current research has focused on animal models, including fish, frog, bird, and mouse, and also studies involving humans. It is also worthwhile to note that the branching morphogenesis of the fly trachea system has been utilized to address fundamental questions of vascular morphogenesis.This chapter will summarize the genomic manipulation of the murine vascular system to address questions regarding vascular development. In addition, the advances that have been made in this field using such methods will be summarized.

scholarly journals G protein-coupled receptor trafficking and signaling: new insights into the enteric nervous system

2019 ◽  
Vol 316 (4) ◽  
pp. G446-G452 ◽  
Author(s):  
Simona E. Carbone ◽  
Nicholas A. Veldhuis ◽  
Arisbel B. Gondin ◽  
Daniel P. Poole
Keyword(s):  
Nervous System ◽  
Enteric Nervous System ◽  
G Protein ◽  
Molecular Mechanisms ◽  
Intestinal Inflammation ◽  
Receptor Expression ◽  
Enteric Neurons ◽  
Future Research ◽  
Detailed Knowledge ◽  
G Protein Coupled

G protein-coupled receptors (GPCRs) are essential for the neurogenic control of gastrointestinal (GI) function and are important and emerging therapeutic targets in the gut. Detailed knowledge of both the distribution and functional expression of GPCRs in the enteric nervous system (ENS) is critical toward advancing our understanding of how these receptors contribute to GI function during physiological and pathophysiological states. Equally important, but less well defined, is the complex relationship between receptor expression, ligand binding, signaling, and trafficking within enteric neurons. Neuronal GPCRs are internalized following exposure to agonists and under pathological conditions, such as intestinal inflammation. However, the relationship between the intracellular distribution of GPCRs and their signaling outputs in this setting remains a “black box”. This review will briefly summarize current knowledge of agonist-evoked GPCR trafficking and location-specific signaling in the ENS and identifies key areas where future research could be focused. Greater understanding of the cellular and molecular mechanisms involved in regulating GPCR signaling in the ENS will provide new insights into GI function and may open novel avenues for therapeutic targeting of GPCRs for the treatment of digestive disorders.

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