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https://www.readbyqxmd.com/read/28515680/trk-receptors-and-neurotrophin-cross-interactions-new-perspectives-toward-manipulating-therapeutic-side-effects
#1
Yazan Haddad, Vojtěch Adam, Zbyněk Heger
Some therapeutic side-effects result from simultaneous activation of homolog receptors by the same ligand. Tropomyosin receptor kinases (TrkA, TrkB and TrkC) play a major role in the development and biology of neurons through neurotrophin signaling. The wide range of cross-interactions between Trk receptors and neurotrophins vary in selectivity, affinity and function. In this study, we discuss new perspectives to the manipulation of side-effects via a better understanding of the cross-interactions at the molecular level, derived by computational methods...
2017: Frontiers in Molecular Neuroscience
https://www.readbyqxmd.com/read/28455963/trkc-promotes-colorectal-cancer-growth-and-metastasis
#2
Min Soo Kim, Kwang Wook Suh, Suntaek Hong, Wook Jin
The current work reveals that TrkC receptor is crucial to many aspects of tumorigenicity and metastasis of cancer. However, with only a few exceptions, such as colorectal cancer (CRC), where suppressing tumorigenic and metastatic ability via expression of TrkC as tumor suppressor have been proposed. These diverse lines of evidence led us to investigate whether TrkC is involved in CRC progression. By using mouse models and molecular biology analyses, we demonstrate that TrkC acts as an activator in tumorigenicity and metastasis of colorectal cancer...
April 20, 2017: Oncotarget
https://www.readbyqxmd.com/read/28440877/bdnf-nt3-regulate-ais-location-and-affect-neuronal-excitability-in-cultured-hippocampal-neurons
#3
Yu Guo, Zi-Jun Su, Yi-Kun Chen, Zhen Chai
Plasticity of the axon initial segment (AIS) has aroused great interest in recent years because it regulates action potential initiation and neuronal excitability. AIS plasticity manifests as modulation of ion channels or variation in AIS structure. However, the mechanisms underlying structural plasticity of the AIS are not well understood. Here, we combined immunofluorescence, patch-clamp recordings, and pharmacological methods in cultured hippocampal neurons to investigate the factors participating in AIS structural plasticity during development...
April 25, 2017: Journal of Neurochemistry
https://www.readbyqxmd.com/read/28404842/an-immortalized-human-dorsal-root-ganglia-cell-line-provides-a-novel-context-to-study-herpes-simplex-virus-type-1-latency-and-reactivation
#4
Nikki M Thellman, Carolyn Botting, Zachary Madaj, Steven J Triezenberg
A defining characteristic of alphaherpesviruses is the establishment of lifelong latency in host sensory ganglia with occasional reactivation causing recurrent lytic infections. As an alternative to rodent models, we explored the use of an immortalized cell line derived from human dorsal root ganglia. HD10.6 cells proliferate by virtue of a transduced tetracycline-regulated v-myc oncogene. In the presence of doxycycline, HD10.6 cells mature to exhibit neuronal morphology and express sensory neuron-associated markers such as neurotrophin receptors TrkA, TrkB, TrkC, and RET and the sensory neurofilament peripherin...
April 12, 2017: Journal of Virology
https://www.readbyqxmd.com/read/28402394/autophagy-and-trkc-nt-3-signaling-joined-forces-boost-the-hypoxic-glioblastoma-cell-survival
#5
Soha Jawhari, Barbara Bessette, Sophie Hombourger, Karine Durand, Aurélie Lacroix, François Labrousse, Marie-Odile Jauberteau, Marie-Hélène Ratinaud, Mireille Verdier
Glioblastoma multiform (GBM), the most common and aggressive primary brain tumor, is characterized by a high degree of hypoxia and resistance to therapy because of its adaptation capacities, including autophagy and growth factors signaling. In this study, we show an efficient hypoxia-induced survival autophagy in four different GBM cell lines (U87MG, M059K, M059J and LN-18) and an activation of a particular neurotrophin signaling pathway. Indeed, the enhancement of both TrkC and NT-3 was followed by downstream p38MAPK phosphorylation, suggesting the occurrence of a survival autocrine loop...
March 31, 2017: Carcinogenesis
https://www.readbyqxmd.com/read/28398601/antidepressant-imipramine-protects-bupivacaine-induced-neurotoxicity-in-dorsal-root-ganglion-neurons-through-co-activation-of-trka-and-trkb
#6
Jianrong Guo, Huan Wang, Qiang Tao, Shiyu Sun, Li Liu, Jianping Zhang, Dawei Yang
PURPOSE: In our work, we used an in vitro culture model to investigate whether antidepressant imipramine (Ip) may protect bupivacaine (Bv)-induced neurotoxicity in mouse dorsal root ganglion (DRG). METHODS: Adult mouse DRG was treated with 5 mM Bv in vitro to induce neurotoxicity. DRG was then pre-treated with Ip, prior to Bv, to examine its effects on protecting Bv-induced DRG apoptosis and neurite degeneration. Ip-induced dynamic changes in Trk receptors, including TrkA/B/C and phosphor (p-)TrkA/B/C, were examined by qPCR and western blot...
April 11, 2017: Journal of Cellular Biochemistry
https://www.readbyqxmd.com/read/28370021/roles-of-neurotrophins-in-skeletal-tissue-formation-and-healing
#7
REVIEW
Yu-Wen Su, Xin-Fu Zhou, Bruce K Foster, Brian L Grills, Jiake Xu, Cory J Xian
Neurotrophins and their receptors are key molecules that are known to be critical in regulating nervous system development and maintenance and have been recognized to be also involved in regulating tissue formation and healing in skeletal tissues. Studies have shown that neurotrophins and their receptors are widely expressed in skeletal tissues, implicated in chondrogenesis, osteoblastogenesis, and osteoclastogenesis, and are also involved in regulating tissue formation and healing events in skeletal tissue...
March 30, 2017: Journal of Cellular Physiology
https://www.readbyqxmd.com/read/28360836/genetic-tracing-of-cav3-2-t-type-calcium-channel-expression-in-the-peripheral-nervous-system
#8
Yinth A Bernal Sierra, Julia Haseleu, Alexey Kozlenkov, Valérie Bégay, Gary R Lewin
Characterizing the distinct functions of the T-type ion channel subunits Cav3.1, 3.2 or 3.3 has proven difficult due to their highly conserved amino-acid sequences and the lack of pharmacological blockers specific for each subunit. To precisely determine the expression pattern of the Cav3.2 channel in the nervous system we generated two knock-in mouse strains that express EGFP or Cre recombinase under the control of the Cav3.2 gene promoter. We show that in the brains of these animals, the Cav3.2 channel is predominantly expressed in the dentate gyrus of the hippocampus...
2017: Frontiers in Molecular Neuroscience
https://www.readbyqxmd.com/read/28347639/neurite-outgrowth-in-cultured-mouse-pelvic-ganglia-effects-of-neurotrophins-and-bladder-tissue
#9
Mari Ekman, Baoyi Zhu, Karl Swärd, Bengt Uvelius
Neurotrophic factors regulate survival and growth of neurons. The urinary bladder is innervated via both sympathetic and parasympathetic neurons located in the major pelvic ganglion. The aim of the present study was to characterize the effects of the neurotrophins nerve growth factor (NGF), brain derived neurotrophic factor (BDNF) and neurotrophin 3 (NT-3) on the sprouting rate of sympathetic and parasympathetic neurites from the female mouse ganglion. The pelvic ganglion was dissected out and attached to a petri dish and cultured in vitro...
March 18, 2017: Autonomic Neuroscience: Basic & Clinical
https://www.readbyqxmd.com/read/28344123/effects-of-campylobacter-jejuni-lipopolysaccharide-on-axonal-injury-in-the-spinal-cord-in-rats
#10
Xusheng Li, Haohao Chen, Hongmiao Tao, Ye Hu, Hongqiang Lou
To explore the effects of Campylobacter jejuni lipopolysaccharide (Cj-LPS) on axonal injury in the spinal cord. Wistar rats were divided into the control (NC) group, model group (Cj-LPS), and LPS antibody group (Anti-LPS). Rats in the NC group were injected with a mixture of normal saline and complete Freund's adjuvant (CFA) while those in Cj-LPS group were injected with Cj-LPS, composed of LPS, CFA, and saline. Rats were sacrificed at 4th week and 6th week after injection, and hematoxylin and eosin (HE) staining was performed on the spinal cord sections...
March 23, 2017: Microbial Pathogenesis
https://www.readbyqxmd.com/read/28335430/a-review-on-ubiquitination-of-neurotrophin-receptors-facts-and-perspectives
#11
REVIEW
Julia Sánchez-Sánchez, Juan Carlos Arévalo
Ubiquitination is a reversible post-translational modification involved in a plethora of different physiological functions. Among the substrates that are ubiquitinated, neurotrophin receptors (TrkA, TrkB, TrkC, and p75(NTR)) have been studied recently. TrkA is the most studied receptor in terms of its ubiquitination, and different E3 ubiquitin ligases and deubiquitinases have been implicated in its ubiquitination, whereas not much is known about the other neurotrophin receptors aside from their ubiquitination...
March 14, 2017: International Journal of Molecular Sciences
https://www.readbyqxmd.com/read/28293395/expression-pattern-of-neurotrophins-and-their-receptors-during-neuronal-differentiation-of-adipose-derived-stem-cells-in-simulated-microgravity-condition
#12
Vajiheh Zarrinpour, Zahra Hajebrahimi, Mojtaba Jafarinia
OBJECTIVES: Studies have confirmed that microgravity, as a mechanical factor, influences both differentiation and function of mesenchymal stem cells. Here we investigated the effects of simulated microgravity on neural differentiation of human adipose-derived stem cells (ADSCs). MATERIALS AND METHODS: We have used a fast rotating clinostat (clinorotation) to simulate microgravity condition. Real-time PCR and flow cytometry analysis were used to evaluate the regulation of neurotrophins, their receptors, and neural markers by simulated microgravity and their impact on neural differentiation of cells...
February 2017: Iranian Journal of Basic Medical Sciences
https://www.readbyqxmd.com/read/28279735/development-of-a-pharmacodynamic-biomarker-to-measure-target-engagement-from-inhibition-of-the-ngf-trka-pathway
#13
Eric A Price, Alicja Krasowska-Zoladek, Kausik K Nanda, Shawn J Stachel, Darrell A Henze
BACKGROUND: NGF signaling through TrkA triggers pathways involved in a wide range of biological effects. Clinical trials targeting either NGF or TrkA are ongoing to treat various diseases in the areas of oncology, neuroscience, and for pain, but there is no described measure of target engagement of TrkA in these studies. NEW METHOD: We have developed custom ELISA assays to measure NGF-induced phosphorylation of TrkA specific for rodent and human receptors. Optimized tissue processing methods allow for detection in both the brain and in skin...
March 7, 2017: Journal of Neuroscience Methods
https://www.readbyqxmd.com/read/28266869/pig-induced-pluripotent-stem-cell-derived-neural-rosettes-parallel-human-differentiation-into-sensory-neural-subtypes
#14
Robin L Webb, Amalia Gallegos-Cárdenas, Colette N Miller, Nicholas J Solomotis, Hong-Xiang Liu, Franklin D West, Steven L Stice
The pig is the large animal model of choice for study of nerve regeneration and wound repair. Availability of porcine sensory neural cells would conceptually allow for analogous cell-based peripheral nerve regeneration in porcine injuries of similar severity and size to those found in humans. After recently reporting that porcine (or pig) induced pluripotent stem cells (piPSCs) differentiate into neural rosette (NR) structures similar to human NRs, here we demonstrate that pig NR cells could differentiate into neural crest cells and other peripheral nervous system-relevant cell types...
April 2017: Cellular Reprogramming
https://www.readbyqxmd.com/read/28215291/crystal-structures-of-neurotrophin-receptors-kinase-domain
#15
T Bertrand
Neurotrophins and their receptors (Trk) play key roles in the development of the nervous system and in cell survival. Trk receptors are therefore attractive pharmacological targets for brain disorders as well as for cancers. While the druggability of the extracellular domain of the receptors, that specifically binds neurotrophins, is yet to be proven, the intracellular kinase domains are attractive targets for small-molecule binding. The recent crystal structures of the three isoforms of the Trk family, TrkA, TrkB, and TrkC have been described in their apo forms and in complex with potent and selective pan-Trk inhibitors...
2017: Vitamins and Hormones
https://www.readbyqxmd.com/read/28174090/targeting-trk-family-proteins-in-cancer
#16
REVIEW
Yekaterina B Khotskaya, Vijaykumar R Holla, Anna F Farago, Kenna R Mills Shaw, Funda Meric-Bernstam, David S Hong
The tropomyosin receptor kinase (TRK) family includes TRKA, TRKB, and TRKC proteins, which are encoded by NTRK1, NTRK2 and NTRK3 genes, respectively. Binding of neurotrophins to TRK proteins induces receptor dimerization, phosphorylation, and activation of the downstream signaling cascades via PI3K, RAS/MAPK/ERK, and PLC-gamma. TRK pathway aberrations, including gene fusions, protein overexpression, and single nucleotide alterations, have been implicated in the pathogenesis of many cancer types, with NTRK gene fusions being the most well validated oncogenic events to date...
February 4, 2017: Pharmacology & Therapeutics
https://www.readbyqxmd.com/read/28159414/the-juxtamembrane-region-of-trka-kinase-is-critical-for-inhibitor-selectivity
#17
Noritaka Furuya, Takaki Momose, Kenji Katsuno, Nobuhiko Fushimi, Hideyuki Muranaka, Chiaki Handa, Tomonaga Ozawa, Takayoshi Kinoshita
Although numerous crystal structures for protein kinases have been reported, many include only the kinase domain but not the juxtamembrane (JM) region, a critical activity-controlling segment of receptor tyrosine kinases (RTKs). In this study, we determined the X-ray crystal structure of the tropomyosin receptor kinase (Trk) A selective inhibitor A1 complexed with the TrkA kinase domain and the JM region. This structure revealed that the unique inhibitor-binding pocket created by a novel JM configuration yields significant potency and high selectivity against TrkB and TrkC...
January 21, 2017: Bioorganic & Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/28133521/activation-of-neurotrophins-in-lumbar-dorsal-root-probably-contributes-to-neuropathic-pain-after-spinal-nerve-ligation
#18
Abdolreza Kazemi, Masoud Rahmati, Rasoul Eslami, Vahid Sheibani
OBJECTIVES: Neurotrophins (NTs) exert various effects on neuronal system. Growing evidence indicates that NTs are involved in the pathophysiology of neuropathic pain. However, the exact role of these proteins in modulating nociceptive signaling requires being defined. Thus, the aim of this study was to evaluate the effects of spinal nerve ligation (SNL) on NTs activation in the lumbar dorsal root. MATERIALS AND METHODS: Ten male Wistar rats were randomly assigned to two groups: tight ligation of the L5 spinal nerve (SNL: n=5) and Sham (n=5)...
January 2017: Iranian Journal of Basic Medical Sciences
https://www.readbyqxmd.com/read/28100780/a-novel-microrna-located-in-the-trkc-gene-regulates-the-wnt-signaling-pathway-and-is-differentially-expressed-in-colorectal-cancer-specimens
#19
Sadat Dokanehiifard, Atena Yasari, Hadi Najafi, Meisam Jafarzadeh, Maryam Nikkhah, Seyed Javad Mowla, Bahram M Soltani
Tropomyosin receptor kinase C (TrkC) is involved in cell survival, apoptosis, differentiation, and tumorigenesis. TrkC diverse functions might be attributed to the hypothetical non-coding RNAs embedded within the gene. Using bioinformatics approaches, a novel microRNA named TrkC-miR2 was predicted within the TrkC gene capable of regulating the Wnt pathway. For experimental verification of this microRNA, the predicted TrkC-premir2 sequence was overexpressed in SW480 cells, which led to the detection of two mature TrkC-miR2 isomiRs, and their endogenous forms were detected in human cell lines as well...
May 5, 2017: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/28039433/structural-characterization-of-nonactive-site-trka-selective-kinase-inhibitors
#20
Hua-Poo Su, Keith Rickert, Christine Burlein, Kartik Narayan, Marina Bukhtiyarova, Danielle M Hurzy, Craig A Stump, Xufang Zhang, John Reid, Alicja Krasowska-Zoladek, Srivanya Tummala, Jennifer M Shipman, Maria Kornienko, Peter A Lemaire, Daniel Krosky, Amanda Heller, Abdelghani Achab, Chad Chamberlin, Peter Saradjian, Berengere Sauvagnat, Xianshu Yang, Michael R Ziebell, Elliott Nickbarg, John M Sanders, Mark T Bilodeau, Steven S Carroll, Kevin J Lumb, Stephen M Soisson, Darrell A Henze, Andrew J Cooke
Current therapies for chronic pain can have insufficient efficacy and lead to side effects, necessitating research of novel targets against pain. Although originally identified as an oncogene, Tropomyosin-related kinase A (TrkA) is linked to pain and elevated levels of NGF (the ligand for TrkA) are associated with chronic pain. Antibodies that block TrkA interaction with its ligand, NGF, are in clinical trials for pain relief. Here, we describe the identification of TrkA-specific inhibitors and the structural basis for their selectivity over other Trk family kinases...
January 17, 2017: Proceedings of the National Academy of Sciences of the United States of America
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