scholarly journals BMP Signaling Downstream of the Highwire E3 Ligase Sensitizes Nociceptors

2018 ◽  
Author(s):  
Ken Honjo ◽  
W. Daniel Tracey
Keyword(s):  
Chronic Pain ◽  
Signaling Pathway ◽  
Sensory Neurons ◽  
Molecular Mechanisms ◽  
Critical Role ◽  
Bmp Signaling ◽  
Sensory Transduction ◽  
Noxious Heat ◽  
Nociceptive Responses ◽  
Bmp Pathway

AbstractA comprehensive understanding of the molecular machinery important for nociception is essential to improving the treatment of pain. Here, we show that the BMP signaling pathway regulates nociception downstream of the E3 ubiquitin ligase highwire (hiw). Hiw loss of function in nociceptors caused antagonistic and pleiotropic phenotypes with simultaneous insensitivity to noxious heat but sensitized responses to optogenetic activation of nociceptors. Thus, hiw functions to both positively and negatively regulate nociceptors. We find that a sensory transduction-independent sensitization pathway was associated with BMP signaling. BMP signaling in nociceptors was up-regulated in hiw mutants, and nociceptor-specific expression of hiw rescued all nociception phenotypes including the increased BMP signaling. Blocking the transcriptional output of the BMP pathway with dominant negative Mad suppressed nociceptive hypersensitivity that was induced by interfering with hiw. The up-regulated BMP signaling phenotype in hiw genetic mutants could not be suppressed by mutation in wallenda suggesting that hiw regulates BMP in nociceptors via a wallenda independent pathway. In a newly established Ca2+ imaging preparation, we observed that up-regulated BMP signaling caused a significantly enhanced Ca2+ signal in the axon terminals of nociceptors that were stimulated by noxious heat. This response likely accounts for the nociceptive hypersensitivity induced by elevated BMP signaling in nociceptors. Finally, we showed that acute activation of BMP signaling in nociceptors was sufficient to sensitize nociceptive responses to optogenetically-triggered nociceptor activation without altering nociceptor morphology. Overall, this study demonstrates the previously unrevealed roles of the Hiw-BMP pathway in the regulation of nociception and provides the first direct evidence that up-regulated BMP signaling physiologically sensitizes responses of nociceptors and nociception behaviors.Author SummaryAlthough pain is a universally experienced sensation that has a significant impact on human lives and society, the molecular mechanisms of pain remain poorly understood. Elucidating these mechanisms is particularly important to gaining insight into the clinical development of currently incurable chronic pain diseases. Taking an advantage of the powerful genetic model organism Drosophila melanogaster (fruit flies), we unveil the Highwire-BMP signaling pathway as a novel molecular pathway that regulates the sensitivity of nociceptive sensory neurons. Highwire and the molecular components of the BMP signaling pathway are known to be widely conserved among animal phyla, from nematode worms to humans. Since abnormal sensitivity of nociceptive sensory neurons can play a critical role in the development of chronic pain conditions, a deeper understanding of the regulation of nociceptor sensitivity has the potential to advance effective therapeutic strategies to treat difficult pain conditions.

scholarly journals BMP signaling controls buckling forces to modulate looping morphogenesis of the gut

2017 ◽  
Vol 114 (9) ◽  
pp. 2277-2282 ◽  
Author(s):  
Nandan L. Nerurkar ◽  
L. Mahadevan ◽  
Clifford J. Tabin
Keyword(s):  
Small Intestine ◽  
Molecular Mechanisms ◽  
Critical Role ◽  
Tissue Level ◽  
Body Cavity ◽  
Bmp Signaling ◽  
The Body ◽  
Differential Growth ◽  
Bmp Pathway ◽  
Dorsal Mesentery

Looping of the initially straight embryonic gut tube is an essential aspect of intestinal morphogenesis, permitting proper placement of the lengthy small intestine within the confines of the body cavity. The formation of intestinal loops is highly stereotyped within a given species and results from differential-growth–driven mechanical buckling of the gut tube as it elongates against the constraint of a thin, elastic membranous tissue, the dorsal mesentery. Although the physics of this process has been studied, the underlying biology has not. Here, we show that BMP signaling plays a critical role in looping morphogenesis of the avian small intestine. We first exploited differences between chicken and zebra finch gut morphology to identify the BMP pathway as a promising candidate to regulate differential growth in the gut. Next, focusing on the developing chick small intestine, we determined that Bmp2 expressed in the dorsal mesentery establishes differential elongation rates between the gut tube and mesentery, thereby regulating the compressive forces that buckle the gut tube into loops. Consequently, the number and tightness of loops in the chick small intestine can be increased or decreased directly by modulation of BMP activity in the small intestine. In addition to providing insight into the molecular mechanisms underlying intestinal development, our findings provide an example of how biochemical signals act on tissue-level mechanics to drive organogenesis, and suggest a possible mechanism by which they can be modulated to achieve distinct morphologies through evolution.

Dorsal Root Ganglion Neuron Types and Their Functional Specialization

2018 ◽  
pp. 127-155 ◽  
Author(s):  
Edward C. Emery ◽  
Patrik Ernfors
Keyword(s):  
Chronic Pain ◽  
Dorsal Root Ganglion ◽  
Sensory Neurons ◽  
Dorsal Root ◽  
Molecular Mechanisms ◽  
Expression Profiles ◽  
Gene Expression Profiles ◽  
Drg Neurons ◽  
Low Threshold

Primary sensory neurons of the dorsal root ganglion (DRG) respond and relay sensations that are felt, such as those for touch, pain, temperature, itch, and more. The ability to discriminate between the various types of stimuli is reflected by the existence of specialized DRG neurons tuned to respond to specific stimuli. Because of this, a comprehensive classification of DRG neurons is critical for determining exactly how somatosensation works and for providing insights into cell types involved during chronic pain. This article reviews the recent advances in unbiased classification of molecular types of DRG neurons in the perspective of known functions as well as predicted functions based on gene expression profiles. The data show that sensory neurons are organized in a basal structure of three cold-sensitive neuron types, five mechano-heat sensitive nociceptor types, four A-Low threshold mechanoreceptor types, five itch-mechano-heat–sensitive nociceptor types and a single C–low-threshold mechanoreceptor type with a strong relation between molecular neuron types and functional types. As a general feature, each neuron type displays a unique and predicable response profile; at the same time, most neuron types convey multiple modalities and intensities. Therefore, sensation is likely determined by the summation of ensembles of active primary afferent types. The new classification scheme will be instructive in determining the exact cellular and molecular mechanisms underlying somatosensation, facilitating the development of rational strategies to identify causes for chronic pain.

scholarly journals Capn4 Enhances Osteopontin Expression through Activation of the Wnt/β-Catenin Pathway to Promote Epithelial Ovarian Carcinoma Metastasis

2017 ◽  
Vol 42 (1) ◽  
pp. 185-197 ◽  
Author(s):  
Xiaoming Yang ◽  
Jing Sun ◽  
Dandan Xia ◽  
Xupei Can ◽  
Lei Liu ◽  
...  
Keyword(s):  
Ovarian Carcinoma ◽  
Signaling Pathway ◽  
Cell Lines ◽  
Western Blotting ◽  
Molecular Mechanisms ◽  
Critical Role ◽  
Epithelial Ovarian Carcinoma ◽  
Regulatory Subunit ◽  
Epithelial Tissue

Background and Aim: Increasing evidence shows that the calpain regulatory subunit Capn4 can modulate the proliferation and metastasis of cancer cells, and plays an important role in the development of malignant tumors. However, there is no information on the clinical significance of Capn4 in epithelial ovarian carcinoma (EOC) or the molecular mechanisms by which Capn4 promotes the growth and metastasis of EOC. Therefore, the aim of this study was to clarify the role of Capn4 in EOC. Methods: We evaluated Capn4 and osteopontin (OPN) expression in EOC cell lines and tissues from patients with ovarian cancer by western blotting and immunohistochemical analysis. We then created cell lines with downregulated and upregulated Capn4 expression, using Capn4-targeting small interfering RNA and a pcDNA3.1-Capn4 overexpression vector, respectively, to investigate its function in EOC in vitro. In addition, we investigated the potential mechanism underlying the function of Capn4 by examining the effect of modifying Capn4 expression on Wnt/β-catenin signaling pathway-related genes by western blotting. Results: Capn4 was overexpressed in clinical EOC tissues compared with that in normal ovarian epithelial tissue, and was associated with poor clinical outcomes. Upon silencing or overexpressing Capn4 in EOC cells, we concluded that Capn4 promotes cell proliferation and migration in vitro. Furthermore, Capn4 promoted EOC metastasis by interacting with the Wnt/β-catenin signaling pathway to upregulate OPN expression. Conclusion: Our study indicates that Capn4 plays a critical role in the progression and metastasis of EOC, and could be a potential therapeutic target for EOC management.

scholarly journals Evidence for the critical role of the PI3K signaling pathway in particulate matter-induced dysregulation of the inflammatory mediators COX-2/PGE2 and the associated epithelial barrier protein Filaggrin in the bronchial epithelium

2019 ◽  
Vol 36 (4) ◽  
pp. 301-313
Author(s):  
Chenjian Song ◽  
Lingjing Liu ◽  
Junjie Chen ◽  
Yiran Hu ◽  
Jingli Li ◽  
...  
Keyword(s):  
Particulate Matter ◽  
Airway Inflammation ◽  
Signaling Pathway ◽  
Molecular Mechanisms ◽  
Transmembrane Protein ◽  
Critical Role ◽  
Pi3k Signaling ◽  
Dependent Manner ◽  
Pi3k Signaling Pathway ◽  
Cox 2

AbstractParticulate matter (PM) is an environmental pollutant closely associated with human airway inflammation. However, the molecular mechanisms of PM-related airway inflammation remains to be fully elucidated. It is known that COX-2/PGE2 play key roles in the pathogenesis of airway inflammation. Filaggrin is a transmembrane protein contributing to tight junction barrier function. As such, Filaggrin prevents leakage of transported solutes and is therefore necessary for the maintenance of epithelial integrity. The objective of the present study was to investigate the regulatory mechanisms of COX-2/PGE2 and Filaggrin upon PM exposure both in vivo and in vitro. C57BL/6 mice received intratracheal instillation of PM for two consecutive days. In parallel, human bronchial epithelial cells (HBECs) were exposed to PM for 24 h. PM exposure resulted in airway inflammation together with upregulation of COX-2/PGE2 and downregulation of Filaggrin in mouse lungs. Corresponding dysregulation of COX-2/PGE2 and Filaggrin was also observed in HBECs subjected to PM. PM exposure led to the phosphorylation of ERK, JNK, and PI3K signaling pathways in a time-dependent manner, while blockade of PI3K with the specific molecular inhibitor LY294002 partially reversed the dysregulation of COX-2/PGE2 and Filaggrin. Moreover, pretreatment of HBECs with NS398, a specific molecular inhibitor of COX-2, and AH6809, a downstream PGE2 receptor inhibitor, reversed the downregulation of Filaggrin upon PM exposure. Taken together, these data demonstrated that the PI3K signaling pathway upregulated COX-2 as well as PGE2 and acted as a pivotal mediator in the downregulation of Filaggrin.

scholarly journals THE GABA-ERGIC SYSTEM DOES NOT CONTROL THE NOCICEPTIVE RESPONSES OF PRIMARY SENSORY NEURON

2019 ◽  
Vol 19 (1S) ◽  
pp. 44-45
Author(s):  
V A Penniyaynen ◽  
S A Podzorova ◽  
S G Terekhin ◽  
B V Krylov ◽  
V B Plakhova
Keyword(s):  
Sensory Neuron ◽  
Sensory Neurons ◽  
Nervous Tissue ◽  
Molecular Mechanisms ◽  
Primary Sensory Neuron ◽  
Nociceptive Neuron ◽  
Wide Range ◽  
Nociceptive Responses ◽  
Activation Gating

The aim of the study was to elucidate the molecular mechanisms of the interconnection of the GABA-ergic and nociceptive systems at the level of the peripheral division of the CNS. The data obtained indicate that GABA does not affect the activation gating device of the NaV1.8 channel of the primary sensory neuron responsible for coding pain signals.This agent in a wide range of concentrations also does not affect the growth of neurites of sensory neurons of embryonic nervous tissue. These results confirm our assumption, expressed earlier that the asynaptic membrane of the primary nociceptive neuron is not under the control of the GABA-ergic system.

scholarly journals The brinker repressor system regulates injury-induced nociceptive sensitization in Drosophila melanogaster

2021 ◽  
Vol 17 ◽  
pp. 174480692110374
Author(s):  
Aidan McParland ◽  
Julie Moulton ◽  
Courtney Brann ◽  
Christine Hale ◽  
Yvonne Otis ◽  
...  
Keyword(s):  
Chronic Pain ◽  
Drosophila Melanogaster ◽  
Signaling Pathway ◽  
Mechanical Pressure ◽  
Nociceptive Sensitization ◽  
Morphogenetic Protein ◽  
Bmp Pathway ◽  
Transcription Regulators ◽  
Hh Signaling ◽  
Pain Signal

Chronic pain is a debilitating condition affecting millions of people worldwide, and an improved understanding of the pathophysiology of chronic pain is urgently needed. Nociceptors are the sensory neurons that alert the nervous system to potentially harmful stimuli such as mechanical pressure or noxious thermal temperature. When an injury occurs, the nociceptive threshold for pain is reduced and an increased pain signal is produced. This process is called nociceptive sensitization. This sensitization normally subsides after the injury is healed. However, dysregulation can occur which results in sensitization that persists after the injury has healed. This process is thought to perpetuate chronic pain. The Hedgehog (Hh) signaling pathway has been previously implicated in nociceptive sensitization in response to injury in Drosophila melanogaster. Downstream of Hh signaling, the Bone Morphogenetic Protein (BMP) pathway has also been shown to be necessary for this process. Here, we describe a role for nuclear components of BMP’s signaling pathway in the formation of injury-induced nociceptive sensitization. Brinker (Brk), and Schnurri (Shn) were suppressed in nociceptors using an RNA-interference (RNAi) “knockdown” approach. Knockdown of Brk resulted in hypersensitivity in the absence of injury, indicating that it normally acts to suppress nociceptive sensitivity. Animals in which transcriptional activator Shn was knocked down in nociceptors failed to develop normal allodynia after ultraviolet irradiation injury, indicating that Shn normally acts to promote hypersensitivity after injury. These results indicate that Brk-related transcription regulators play a crucial role in the formation of nociceptive sensitization and may therefore represent valuable new targets for pain-relieving medications.

scholarly journals Brain-derived neurotrophic factor derived from sensory neurons plays a critical role in chronic pain

Brain ◽  
2018 ◽  
Vol 141 (4) ◽  
pp. 1028-1039 ◽  
Author(s):  
Shafaq Sikandar ◽  
Michael S Minett ◽  
Queensta Millet ◽  
Sonia Santana-Varela ◽  
Joanne Lau ◽  
...  
Keyword(s):  
Chronic Pain ◽  
Sensory Neurons ◽  
Neurotrophic Factor ◽  
Critical Role ◽  
Brain Derived Neurotrophic Factor

scholarly journals TMEM165 a new player in proteoglycan synthesis: loss of TMEM165 impairs elongation of chondroitin- and heparan-sulfate glycosaminoglycan chains of proteoglycans and triggers early chondrocyte differentiation and hypertrophy

2021 ◽  
Vol 13 (1) ◽  
Author(s):  
Sajida Khan ◽  
Malak Sbeity ◽  
François Foulquier ◽  
Lydia Barré ◽  
Mohamed Ouzzine
Keyword(s):  
Heparan Sulfate ◽  
Therapeutic Strategy ◽  
Molecular Mechanisms ◽  
Critical Role ◽  
Bmp Signaling ◽  
Proteoglycan Synthesis ◽  
Fibroblast Cells ◽  
Chondrocyte Maturation ◽  
Elongation Process

AbstractTMEM165 deficiency leads to skeletal disorder characterized by major skeletal dysplasia and pronounced dwarfism. However, the molecular mechanisms involved have not been fully understood. Here, we uncover that TMEM165 deficiency impairs the synthesis of proteoglycans by producing a blockage in the elongation of chondroitin-and heparan-sulfate glycosaminoglycan chains leading to the synthesis of proteoglycans with shorter glycosaminoglycan chains. We demonstrated that the blockage in elongation of glycosaminoglycan chains is not due to defect in the Golgi elongating enzymes but rather to availability of the co-factor Mn2+. Supplementation of cell with Mn2+ rescue the elongation process, confirming a role of TMEM165 in Mn2+ Golgi homeostasis. Additionally, we showed that TMEM165 deficiency functionally impairs TGFβ and BMP signaling pathways in chondrocytes and in fibroblast cells of TMEM165 deficient patients. Finally, we found that loss of TMEM165 impairs chondrogenic differentiation by accelerating the timing of Ihh expression and promoting early chondrocyte maturation and hypertrophy. Collectively, our results indicate that TMEM165 plays an important role in proteoglycan synthesis and underline the critical role of glycosaminoglycan chains structure in the regulation of chondrogenesis. Our data also suggest that Mn2+ supplementation may be a promising therapeutic strategy in the treatment of TMEM165 deficient patients.

chGRP78 is Required for the Activation and Phosphorylation of AKT1 at Serine 478 in Chicken Sells

2021 ◽  
Author(s):  
H. Choi ◽  
Y.D. Kim ◽  
S.K. Jung ◽  
S. Sureshkumar ◽  
K.B. Oh ◽  
...  
Keyword(s):  
Signaling Pathway ◽  
Binding Sites ◽  
Chicken Embryo ◽  
Molecular Mechanisms ◽  
Chicken Embryo Fibroblast ◽  
Critical Role ◽  
Fibroblast Cells ◽  
Chicken Serum ◽  
2D Gel ◽  
Chicken Fibroblast

Background: Chicken serum-mediated proliferation regulates chGRP78 to prevent apoptosis in chicken cells via chGRP78-mediated anti-apoptosis. However, the precise molecular mechanisms underlying the chGRP78-mediated protection against apoptosis remain undefined. In an earlier study, we have shown that chGRP78 is critical for chicken embryo fibroblast (CEF) and DF-1 cell proliferation.Methods: In this experiment, we highlight AKT1 as a key target of GRP78 during apoptosis. We used 2D gel-based proteomics and bioinformatics prediction analysis for our studies. Result: Here, we detected chGRP78 binding sites in AKT1-rgulated proteins. chGRP78 promoted AKT1 activation and chGRP78 silencing decreased AKT1 levels. Taken together, we suggest that the AKT1-mediated signaling pathway plays a critical role in GRP78-stimulated fibroblast survival and anti-apoptosis. Our findings have important implications for the maintenance of chicken fibroblast cells via the inhibition of apoptosis.

scholarly journals Aberrant BMP2 Signaling in Patients Diagnosed with Osteoporosis

2020 ◽  
Vol 21 (18) ◽  
pp. 6909 ◽  
Author(s):  
Hilary W. Durbano ◽  
Daniel Halloran ◽  
John Nguyen ◽  
Victoria Stone ◽  
Sean McTague ◽  
...  
Keyword(s):  
Signaling Pathway ◽  
Bmp Signaling ◽  
Bone Morphogenetic Protein 2 ◽  
Osteoblast Activity ◽  
Morphogenetic Protein ◽  
Osteogenic Response ◽  
Type Ia ◽  
Bmp Pathway ◽  
Negative Side Effects ◽  
Potent Growth

The most common bone disease in humans is osteoporosis (OP). Current therapeutics targeting OP have several negative side effects. Bone morphogenetic protein 2 (BMP2) is a potent growth factor that is known to activate both osteoblasts and osteoclasts. It completes these actions through both SMAD-dependent and SMAD-independent signaling. A novel interaction between the BMP type Ia receptor (BMPRIa) and casein kinase II (CK2) was discovered, and several CK2 phosphorylation sites were identified. A corresponding blocking peptide (named CK2.3) was designed to further elucidate the phosphorylation site’s function. Previously, CK2.3 demonstrated an increased osteoblast activity and decreased osteoclast activity in a variety of animal models, cell lines, and isolated human osteoblasts. It is hypothesized that CK2.3 completes these actions through the BMP signaling pathway. Furthermore, it was recently discovered that BMP2 did not elicit an osteogenic response in osteoblasts from patients diagnosed with OP, while CK2.3 did. In this study, we explore where in the BMP pathway the signaling disparity or defect lies in those diagnosed with OP. We found that osteoblasts isolated from patients diagnosed with OP did not activate SMAD or ERK signaling after BMP2 stimulation. When OP osteoblasts were stimulated with BMP2, both BMPRIa and CK2 expression significantly decreased. This indicates a major disparity within the BMP signaling pathway in patients diagnosed with osteoporosis.

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