Abstract
N-methyl-D-aspartate receptors (NMDAR) have a recognized role in neuronal plasticity while their excessive activation results in excitotoxic death. Therefore, NMDAR antagonists are considered for neuroprotective interventions. However, there is also an emerging role of NMDAR in supporting neuronal survival. Thus, during CNS development, basal NMDAR activity suppresses neuronal apoptosis while moderate NMDAR activation may, at least under some conditions, protect against excitotoxic/ischemic insults. These suggest that while protecting from excitotoxicity, NMDAR antagonists would also reduce pro-survival activity of NMDAR. Hence, the identification of the switches controlling prosurvival vs. pro-excitotoxic outcome of NMDAR stimulation may lead to development of NMDAR antagonists that selectively block the excitotoxicity while enhancing the protective NMDAR signaling. On the other hand, the existence of anti-apoptotic/pro-proliferative NMDAR signaling in transformed cells may result in new strategies to attack cancer. This review focuses on the emerging field of neuroprotective signaling mediators that are implicated in pro-survival activity of NMDAR. We discuss the evidence implicating either NR2B or nonNR2B NMDAR in mediating the protection. We also present the reports linking NMDAR-mediated protection to the activation of survival signaling kinases including ERK and Akt, or suppression of a pro-apoptotic kinase, GSK-3β. The protective role of transcription factors is also discussed. Finally, we review the existing evidence suggesting that NMDAR support survival by regulating the pro-survival trophic factor signaling and/or the cell death machinery. Although NMDAR provide a major survival input to CNS neurons, the NMDAR-activated protective signaling is poorly understood and, therefore, deserves further research effort.
Keywords: glutamate receptors, glutamate, BDNF, GSK-3β, ERK, Akt, CREB, apoptosis, cell death, neuroprotection
Current Topics in Medicinal Chemistry
Title: Survival Signaling Pathways Activated by NMDA Receptors
Volume: 6 Issue: 8
Author(s): Michal Hetman and Giorgi Kharebava
Affiliation:
Keywords: glutamate receptors, glutamate, BDNF, GSK-3β, ERK, Akt, CREB, apoptosis, cell death, neuroprotection
Abstract: N-methyl-D-aspartate receptors (NMDAR) have a recognized role in neuronal plasticity while their excessive activation results in excitotoxic death. Therefore, NMDAR antagonists are considered for neuroprotective interventions. However, there is also an emerging role of NMDAR in supporting neuronal survival. Thus, during CNS development, basal NMDAR activity suppresses neuronal apoptosis while moderate NMDAR activation may, at least under some conditions, protect against excitotoxic/ischemic insults. These suggest that while protecting from excitotoxicity, NMDAR antagonists would also reduce pro-survival activity of NMDAR. Hence, the identification of the switches controlling prosurvival vs. pro-excitotoxic outcome of NMDAR stimulation may lead to development of NMDAR antagonists that selectively block the excitotoxicity while enhancing the protective NMDAR signaling. On the other hand, the existence of anti-apoptotic/pro-proliferative NMDAR signaling in transformed cells may result in new strategies to attack cancer. This review focuses on the emerging field of neuroprotective signaling mediators that are implicated in pro-survival activity of NMDAR. We discuss the evidence implicating either NR2B or nonNR2B NMDAR in mediating the protection. We also present the reports linking NMDAR-mediated protection to the activation of survival signaling kinases including ERK and Akt, or suppression of a pro-apoptotic kinase, GSK-3β. The protective role of transcription factors is also discussed. Finally, we review the existing evidence suggesting that NMDAR support survival by regulating the pro-survival trophic factor signaling and/or the cell death machinery. Although NMDAR provide a major survival input to CNS neurons, the NMDAR-activated protective signaling is poorly understood and, therefore, deserves further research effort.
Export Options
About this article
Cite this article as:
Hetman Michal and Kharebava Giorgi, Survival Signaling Pathways Activated by NMDA Receptors, Current Topics in Medicinal Chemistry 2006; 6 (8) . https://dx.doi.org/10.2174/156802606777057553
DOI https://dx.doi.org/10.2174/156802606777057553 |
Print ISSN 1568-0266 |
Publisher Name Bentham Science Publisher |
Online ISSN 1873-4294 |
Call for Papers in Thematic Issues
AlphaFold in Medicinal Chemistry: Opportunities and Challenges
AlphaFold, a groundbreaking AI tool for protein structure prediction, is revolutionizing drug discovery. Its near-atomic accuracy unlocks new avenues for designing targeted drugs and performing efficient virtual screening. However, AlphaFold's static predictions lack the dynamic nature of proteins, crucial for understanding drug action. This is especially true for multi-domain proteins, ...read more
Artificial intelligence for Natural Products Discovery and Development
Our approach involves using computational methods to predict the potential therapeutic benefits of natural products by considering factors such as drug structure, targets, and interactions. We also employ multitarget analysis to understand the role of drug targets in disease pathways. We advocate for the use of artificial intelligence in predicting ...read more
Chemistry Based on Natural Products for Therapeutic Purposes
The development of new pharmaceuticals for a wide range of medical conditions has long relied on the identification of promising natural products (NPs). There are over sixty percent of cancer, infectious illness, and CNS disease medications that include an NP pharmacophore, according to the Food and Drug Administration. Since NP ...read more
Current Trends in Drug Discovery Based on Artificial Intelligence and Computer-Aided Drug Design
Drug development discovery has faced several challenges over the years. In fact, the evolution of classical approaches to modern methods using computational methods, or Computer-Aided Drug Design (CADD), has shown promising and essential results in any drug discovery campaign. Among these methods, molecular docking is one of the most notable ...read more
- Author Guidelines
- Graphical Abstracts
- Fabricating and Stating False Information
- Research Misconduct
- Post Publication Discussions and Corrections
- Publishing Ethics and Rectitude
- Increase Visibility of Your Article
- Archiving Policies
- Peer Review Workflow
- Order Your Article Before Print
- Promote Your Article
- Manuscript Transfer Facility
- Editorial Policies
- Allegations from Whistleblowers
- Announcements
Related Articles
-
Estrogen Receptor Signaling: Impact on Cell Functions
Current Signal Transduction Therapy High-throughput Screening Identifies Small Molecule Inhibitors of Molecular Chaperones
Current Pharmaceutical Design Influence of Trishomocubanes on Sigma Receptor Binding of N-(1-Benzylpiperidin- 4-yl)-4-[123I]iodobenzamide In Vivo in the Rat Brain
Medicinal Chemistry Therapeutic Trials in Human Transmissible Spongiform Encephalopathies: Recent Advances and Problems to Address
Infectious Disorders - Drug Targets Immunology Behind Tumors: A Mini Review
Current Cancer Therapy Reviews The Proteasome in Health and Disease
Current Pharmaceutical Design Inhibition of Brain Ischemia-Caused Notch Activation in Microglia May Contribute to Isoflurane Postconditioning-Induced Neuroprotection in Male Rats
CNS & Neurological Disorders - Drug Targets Inhibition of Aurora A Kinase by Alisertib Induces Autophagy and Cell Cycle Arrest and Increases Chemosensitivity in Human Hepatocellular Carcinoma HepG2 Cells
Current Cancer Drug Targets The Cytoskeleton as a Therapeutic Target in Childhood Acute Leukemia:Obstacles and Opportunities
Current Drug Targets The Cyclin-Dependent Kinase Inhibitor p21CDKN1A as a Target of Anti-Cancer Drugs
Current Cancer Drug Targets Tubulin-Independent Tau in Alzheimer’s Disease and Cancer: Implications for Disease Pathogenesis and Treatment
Current Alzheimer Research Current Progresses on Nanodelivery Systems for the Treatment of Neuropsychiatric Diseases: Alzheimer’s and Schizophrenia
Current Pharmaceutical Design Reversible and Irreversible Aggregation of Proteins from the FET Family: Influence of Repeats in Protein Chain on Its Aggregation Capacity
Current Protein & Peptide Science P53 Family: At the Crossroads in Cancer Therapy
Current Medicinal Chemistry The Renin-Angiotensin System and Advanced Glycation End-Products in Diabetic Retinopathy: Impacts and Synergies.
Current Clinical Pharmacology Bone Marrow Mesenchymal Stem Cells: Agents of Immunomodulation and Neuroprotection
Current Stem Cell Research & Therapy Opioid-modulating Peptides: Mechanisms of Action
Current Topics in Medicinal Chemistry Preliminary Study on Major Phenolic Groups, Antioxidant and Cytotoxic Capacity of Tuckeroo (<i>Cupaniopsis Anacardioides</i>) Fruit Extracts
Current Nutraceuticals An Update on the Other Telomerase Inhibitors: Non-G-Quadruplex Interactive Agent, Non-Antisense, Non-Reverse Transcriptase Telomerase Inhibitors
Medicinal Chemistry Reviews - Online (Discontinued) Role of the Sex Hormone Estrogen in the Prevention of Lipid Disorder
Current Medicinal Chemistry