Expression changes in mouse brains following nicotine-induced seizures: the modulation of transcription factor networks

2007 ◽  
Vol 30 (3) ◽  
pp. 242-252 ◽  
Author(s):  
Merav Kedmi ◽  
Avi Orr-Urtreger
Keyword(s):  
Transcription Factor ◽  
Nicotinic Acetylcholine Receptors ◽  
Acetylcholine Receptors ◽  
Molecular Mechanisms ◽  
Serum Response Factor ◽  
Seizure Activity ◽  
Transcriptional Response ◽  
Bioinformatic Analysis ◽  
Regulatory Elements ◽  
Promoter Regions

Nicotine, acting through the neuronal nicotinic acetylcholine receptors (nAChRs), can induce seizures in mice. We aimed to study brain transcriptional response to seizure and to identify genes whose expression is altered after nicotine-induced seizures. Whole brains of untreated mice were compared with brains 1 h after seizure activity, using Affymetrix U74Av2 microarrays. Experimental groups included wild-type mice and both nicotine-induced seizure-sensitive and -resistant nAChR mutant mice. Each genotype group received different nicotine doses to generate seizures. This approach allowed the identification of significantly changed genes whose expression was dependent on seizure activity, nicotine administration, or both but not on the type of nAChR subunit mutation or the amount of nicotine injected. Significant expression changes were detected in 62 genes ( P < 0.05, false discovery rate correction). Among them, gene ontology functional annotation analysis determined that the most significantly overrepresented categories were of genes encoding MAP kinase phosphatases, regulators of transcription and nucleosome assembly proteins. In silico bioinformatic analysis of the promoter regions of the 62 changed genes detected significant enrichments of 16 transcription regulatory elements (TREs), creating a network of transcriptional regulatory responses to seizures. The TREs for activating transcription factor and serum response factor were most significantly enriched, supporting their association with seizure activity. Our data suggest that nicotine-induced seizure in mice is a useful model to study seizure activity and its global brain transcriptional response. The differentially expressed genes detected here can help us to understand the molecular mechanisms underlying seizures in animal models and may also serve as candidate genes to study epilepsy in humans.

BDNF and nicotine dependence: associations and potential mechanisms

2020 ◽  
Vol 0 (0) ◽  
Author(s):  
Zeyi Huang ◽  
Daichao Wu ◽  
Xilin Qu ◽  
Meixiang Li ◽  
Ju Zou ◽  
...  
Keyword(s):  
Nicotine Dependence ◽  
Nicotinic Acetylcholine Receptors ◽  
Acetylcholine Receptors ◽  
Molecular Mechanisms ◽  
Public Health Problem ◽  
Nicotine Addiction ◽  
Tyrosine Kinase Receptor ◽  
Bdnf Expression ◽  
High Affinity Receptor ◽  
The Brain

AbstractSmoking is the leading preventable cause of death worldwide and tobacco addiction has become a serious public health problem. Nicotine is the main addictive component of tobacco, and the majority of people that smoke regularly develop nicotine dependence. Nicotine addiction is deemed to be a chronic mental disorder. Although it is well known that nicotine binds to the nicotinic acetylcholine receptors (nAChRs) and activates the mesolimbic dopaminergic system (MDS) to generate the pleasant and rewarding effects, the molecular mechanisms of nicotine addiction are not fully understood. Brain-derived neurotrophic factor (BDNF) is the most prevalent growth factor in the brain, which regulates neuron survival, differentiation, and synaptic plasticity, mainly through binding to the high affinity receptor tyrosine kinase receptor B (TrkB). BDNF gene polymorphisms are associated with nicotine dependence and blood BDNF levels are altered in smokers. In this review, we discussed the effects of nicotine on BDNF expression in the brain and summarized the underlying signaling pathways, which further indicated BDNF as a key regulator in nicotine dependence. Further studies that aim to understand the neurobiological mechanism of BDNF in nicotine addcition would provide a valuable reference for quitting smoking and developing the treatment of other addictive substances.

scholarly journals Nicotine Induces Polyspermy in Sea Urchin Eggs through a Non-Cholinergic Pathway Modulating Actin Dynamics

Cells ◽  
2019 ◽  
Vol 9 (1) ◽  
pp. 63 ◽  
Author(s):  
Nunzia Limatola ◽  
Filip Vasilev ◽  
Luigia Santella ◽  
Jong Tai Chun
Keyword(s):  
Sea Urchin ◽  
Nicotinic Acetylcholine Receptors ◽  
Acetylcholine Receptors ◽  
Molecular Mechanisms ◽  
Actin Dynamics ◽  
Dependent Manner ◽  
Animal Cells ◽  
Sea Urchin Eggs ◽  
Cholinergic Pathway ◽  
Dose Dependent

While alkaloids often exert unique pharmacological effects on animal cells, exposure of sea urchin eggs to nicotine causes polyspermy at fertilization in a dose-dependent manner. Here, we studied molecular mechanisms underlying the phenomenon. Although nicotine is an agonist of ionotropic acetylcholine receptors, we found that nicotine-induced polyspermy was neither mimicked by acetylcholine and carbachol nor inhibited by specific antagonists of nicotinic acetylcholine receptors. Unlike acetylcholine and carbachol, nicotine uniquely induced drastic rearrangement of egg cortical microfilaments in a dose-dependent way. Such cytoskeletal changes appeared to render the eggs more receptive to sperm, as judged by the significant alleviation of polyspermy by latrunculin-A and mycalolide-B. In addition, our fluorimetric assay provided the first evidence that nicotine directly accelerates polymerization kinetics of G-actin and attenuates depolymerization of preassembled F-actin. Furthermore, nicotine inhibited cofilin-induced disassembly of F-actin. Unexpectedly, our results suggest that effects of nicotine can also be mediated in some non-cholinergic pathways.

scholarly journals Structure-Function of Neuronal Nicotinic Acetylcholine Receptor Inhibitors Derived From Natural Toxins

2020 ◽  
Vol 14 ◽  
Author(s):  
Thao N. T. Ho ◽  
Nikita Abraham ◽  
Richard J. Lewis
Keyword(s):  
Drug Design ◽  
Ligand Binding ◽  
Nicotinic Acetylcholine Receptors ◽  
Acetylcholine Receptors ◽  
Molecular Mechanisms ◽  
Rational Drug Design ◽  
Comprehensive Overview ◽  
Nicotinic Acetylcholine ◽  
Structure Based Drug Design ◽  
Selective Ligand

Neuronal nicotinic acetylcholine receptors (nAChRs) are prototypical cation-selective, ligand-gated ion channels that mediate fast neurotransmission in the central and peripheral nervous systems. nAChRs are involved in a range of physiological and pathological functions and hence are important therapeutic targets. Their subunit homology and diverse pentameric assembly contribute to their challenging pharmacology and limit their drug development potential. Toxins produced by an extensive range of algae, plants and animals target nAChRs, with many proving pivotal in elucidating receptor pharmacology and biochemistry, as well as providing templates for structure-based drug design. The crystal structures of these toxins with diverse chemical profiles in complex with acetylcholine binding protein (AChBP), a soluble homolog of the extracellular ligand-binding domain of the nAChRs and more recently the extracellular domain of human α9 nAChRs, have been reported. These studies have shed light on the diverse molecular mechanisms of ligand-binding at neuronal nAChR subtypes and uncovered critical insights useful for rational drug design. This review provides a comprehensive overview and perspectives obtained from structure and function studies of diverse plant and animal toxins and their associated inhibitory mechanisms at neuronal nAChRs.

scholarly journals Identification and characterization of the bZIP transcription factor family in yellowhorn

2020 ◽  
Vol 32 (1) ◽  
pp. 273-284 ◽  
Author(s):  
Qiaoying Chang ◽  
Xin Lu ◽  
Zhi Liu ◽  
Zhimin Zheng ◽  
Song Yu
Keyword(s):  
Transcription Factor ◽  
Leucine Zipper ◽  
Molecular Mechanisms ◽  
Bzip Transcription Factor ◽  
Biological Functions ◽  
Transcription Factor Family ◽  
Promoter Regions ◽  
Basic Leucine Zipper ◽  
Biotic Stresses ◽  
Bzip Transcription Factor Family

AbstractThe basic leucine zipper (bZIP) transcription factor family is one of the largest and most diverse families in plants, regulating plant growth and development and playing an essential role in response to abiotic and biotic stresses. However, little is known about the biological functions of bZIP proteins in yellowhorn (Xanthoceras sorbifolium). Recently, 64 XsbZIP genes were identified in the yellowhorn genome and found to be disproportionately distributed in linkage groups. The XsbZIP proteins clustered into 11 groups based on their phylogenetic relationships with AtbZIP, ZmbZIP and GmbZIP proteins. Five intron patterns in the basic and hinge regions and additional conserved motifs were defined, both supporting the group classification and possibly contributing to their functional diversity. Compared to tandem duplication, the segment duplication greatly contributed to the expansion of yellowhorn bZIP genes. In addition, most XsbZIP genes harbor several stress responsive cis-elements in their promoter regions. Moreover, the RNA-seq and qRT-PCR data indicated XsbZIP genes were extensively involved in response to various stresses, including salt (NaCl), cold and abscisic acid, with possibly different molecular mechanisms. These results provide a new understanding of the biological functions of bZIP transcription factors in yellowhorn.

scholarly journals Genome-wide mRNA profiling identifies X-box-binding protein 1 (XBP1) as an IRE1 and PUMA repressor

2021 ◽  
Author(s):  
Magdalena Gebert ◽  
Aleksandra Sobolewska ◽  
Sylwia Bartoszewska ◽  
Aleksandra Cabaj ◽  
David K. Crossman ◽  
...  
Keyword(s):  
Transcription Factor ◽  
Er Stress ◽  
Cell Line ◽  
Molecular Mechanisms ◽  
Binding Protein ◽  
Bioinformatic Analysis ◽  
Competitive Inhibitor ◽  
Human Cell Line ◽  
Factor X ◽  
Stress Induction

AbstractAccumulation of misfolded proteins in ER activates the unfolded protein response (UPR), a multifunctional signaling pathway that is important for cell survival. The UPR is regulated by three ER transmembrane sensors, one of which is inositol-requiring protein 1 (IRE1). IRE1 activates a transcription factor, X-box-binding protein 1 (XBP1), by removing a 26-base intron from XBP1 mRNA that generates spliced XBP1 mRNA (XBP1s). To search for XBP1 transcriptional targets, we utilized an XBP1s-inducible human cell line to limit XBP1 expression in a controlled manner. We also verified the identified XBP1-dependent genes with specific silencing of this transcription factor during pharmacological ER stress induction with both an N-linked glycosylation inhibitor (tunicamycin) and a non-competitive inhibitor of the sarco/endoplasmic reticulum Ca2+ ATPase (SERCA) (thapsigargin). We then compared those results to the XBP1s-induced cell line without pharmacological ER stress induction. Using next‐generation sequencing followed by bioinformatic analysis of XBP1-binding motifs, we defined an XBP1 regulatory network and identified XBP1 as a repressor of PUMA (a proapoptotic gene) and IRE1 mRNA expression during the UPR. Our results indicate impairing IRE1 activity during ER stress conditions accelerates cell death in ER-stressed cells, whereas elevating XBP1 expression during ER stress using an inducible cell line correlated with a clear prosurvival effect and reduced PUMA protein expression. Although further studies will be required to test the underlying molecular mechanisms involved in the relationship between these genes with XBP1, these studies identify a novel repressive role of XBP1 during the UPR.

scholarly journals Nicotinic Acetylcholine Receptors as Potential Tumor Biomarkers in Genitourinary Cancers: a Review Study

2021 ◽  
Vol 1 (1) ◽  
pp. 4-4
Author(s):  
Khalil Hajiasgharzadeh ◽  
Behzad Baradaran ◽  
Leili Aghebati Maleki ◽  
Alireza Khabbazi
Keyword(s):  
Nicotinic Acetylcholine Receptors ◽  
Acetylcholine Receptors ◽  
Molecular Mechanisms ◽  
Predictive Biomarkers ◽  
Relevant Information ◽  
Nicotinic Acetylcholine ◽  
Multiple Tumor ◽  
Review Study ◽  
Genitourinary Cancers

The genitourinary tissues express the different subtypes of nicotinic acetylcholine receptors (nAChRs), which are involved in many physiologic and pathologic processes. New studies have indicated the significant role of nAChRs in multiple tumor-related properties in different types of malignancies. Genitourinary cancers (GUCs) represent a heterogeneous population of cancers, in both histology and approach to treatment. nAChRs are functionally expressed by a variety of immune cells, tumor cells, and tumor-associated cells in the microenvironment of GUCs. In the current review study, publications until May 2021 were included in the literature review to summarize the potential effects and clinical and experimental significance of nAChRs in GUCs pathogenesis. The results yielded substantial and some paradoxical evidence regard the role of different subtypes of nAChRs as potential regulators and predictive biomarkers for GUCs. The accumulated evidence demonstrated that nAChRs levels were increased in the GUCs samples, which provides clinically relevant information on utilizing nAChRs as a new biomarker to improve the prognosis of these cancers. Also, activation or blockade of these receptors may lead to different downstream signaling pathways and cause diverse effects. Regarding the significant global burden of GUCs, evaluation of these receptors and delineating their molecular mechanisms could enrich our understanding of the biology of GUCs and may have new opportunities for clinical impacts.

scholarly journals Inhibition of α9α10 nicotinic acetylcholine receptors prevents chemotherapy-induced neuropathic pain

2017 ◽  
Vol 114 (10) ◽  
pp. E1825-E1832 ◽  
Author(s):  
Haylie K. Romero ◽  
Sean B. Christensen ◽  
Lorenzo Di Cesare Mannelli ◽  
Joanna Gajewiak ◽  
Renuka Ramachandra ◽  
...  
Keyword(s):  
Neuropathic Pain ◽  
Nicotinic Acetylcholine Receptors ◽  
Acetylcholine Receptors ◽  
Molecular Mechanisms ◽  
Underlying Mechanism ◽  
Nicotinic Acetylcholine ◽  
Cold Allodynia ◽  
Beneficial Effects ◽  
Oxaliplatin Treatment ◽  
Nonmalignant Pain

Opioids are first-line drugs for moderate to severe acute pain and cancer pain. However, these medications are associated with severe side effects, and whether they are efficacious in treatment of chronic nonmalignant pain remains controversial. Medications that act through alternative molecular mechanisms are critically needed. Antagonists of α9α10 nicotinic acetylcholine receptors (nAChRs) have been proposed as an important nonopioid mechanism based on studies demonstrating prevention of neuropathology after trauma-induced nerve injury. However, the key α9α10 ligands characterized to date are at least two orders of magnitude less potent on human vs. rodent nAChRs, limiting their translational application. Furthermore, an alternative proposal that these ligands achieve their beneficial effects by acting as agonists of GABABreceptors has caused confusion over whether blockade of α9α10 nAChRs is the fundamental underlying mechanism. To address these issues definitively, we developed RgIA4, a peptide that exhibits high potency for both human and rodent α9α10 nAChRs, and was at least 1,000-fold more selective for α9α10 nAChRs vs. all other molecular targets tested, including opioid and GABABreceptors. A daily s.c. dose of RgIA4 prevented chemotherapy-induced neuropathic pain in rats. In wild-type mice, oxaliplatin treatment produced cold allodynia that could be prevented by RgIA4. Additionally, in α9 KO mice, chemotherapy-induced development of cold allodynia was attenuated and the milder, temporary cold allodynia was not relieved by RgIA4. These findings establish blockade of α9-containing nAChRs as the basis for the efficacy of RgIA4, and that α9-containing nAChRs are a critical target for prevention of chronic cancer chemotherapy-induced neuropathic pain.

Molecular Mechanisms and Binding Site Location for the Noncompetitive Antagonist Crystal Violet on Nicotinic Acetylcholine Receptors†

Biochemistry ◽  
2006 ◽  
Vol 45 (7) ◽  
pp. 2014-2026 ◽  
Author(s):  
Hugo R. Arias ◽  
Pankaj Bhumireddy ◽  
Guillermo Spitzmaul ◽  
James R. Trudell ◽  
Cecilia Bouzat
Keyword(s):  
Binding Site ◽  
Crystal Violet ◽  
Nicotinic Acetylcholine Receptors ◽  
Acetylcholine Receptors ◽  
Molecular Mechanisms ◽  
Site Location ◽  
Nicotinic Acetylcholine

scholarly journals Molecular Mechanisms of Chlorhexidine Tolerance in Burkholderia cenocepacia Biofilms

2011 ◽  
Vol 55 (5) ◽  
pp. 1912-1919 ◽  
Author(s):  
Tom Coenye ◽  
Heleen Van Acker ◽  
Elke Peeters ◽  
Andrea Sass ◽  
Silvia Buroni ◽  
...  
Keyword(s):  
Burkholderia Cepacia ◽  
Molecular Mechanisms ◽  
Antimicrobial Agents ◽  
Efflux Pump ◽  
Transcriptional Response ◽  
Regulatory Elements ◽  
Burkholderia Cenocepacia ◽  
Phenotypic Analysis ◽  
Content Type ◽  
Sessile Cells

ABSTRACTThe high tolerance of biofilm-grownBurkholderia cepaciacomplex bacteria against antimicrobial agents presents considerable problems for the treatment of infected cystic fibrosis patients and the implementation of infection control guidelines. In the present study, we analyzed the tolerance of planktonic and sessileBurkholderia cenocepaciaJ2315 cultures and examined the transcriptional response of sessile cells to treatment with chlorhexidine. At low (0.0005%) and high (0.05%) concentrations, chlorhexidine had a similar effect on both populations, but at intermediate concentrations (0.015%) the antimicrobial activity was more pronounced in planktonic cultures. The exposure of sessile cells to chlorhexidine resulted in an upregulation of the transcription of 469 (6.56%) and the downregulation of 257 (3.59%) protein-coding genes. A major group of upregulated genes in the treated biofilms encoded membrane-related and regulatory proteins. In addition, several genes coding for drug resistance determinants also were upregulated. The phenotypic analysis of RND (resistance-nodulation-division) efflux pump mutants suggests the presence of lifestyle-specific chlorhexidine tolerance mechanisms; efflux system RND-4 (BCAL2820-BCAL2822) was more responsible for chlorhexidine tolerance in planktonic cells, while other systems (RND-3 [BCAL1672-BCAL1676] and RND-9 [BCAM1945-BCAM1947]) were linked to resistance in sessile cells. After sessile cell exposure, multiple genes encoding chemotaxis and motility-related proteins were upregulated in concert with the downregulation of an adhesin-encoding gene (BCAM2143), suggesting that sessile cells tried to escape the biofilm. We also observed the differential expression of 19 genes carying putative small RNA molecules, indicating a novel role for these regulatory elements in chlorhexidine tolerance.

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