Abstract
Glutamate receptors of the N-methyl-D-asparate (NMDA-) subtype are tetrameric allosteric and ligand-gated calcium channels. They are modulated by a variety of endogenous ligands and ions and play a pivotal role in memoryrelated signal transduction due to a voltage-dependent block by magnesium, which makes them Hebbian coincidence detectors. On the structural level NMDA receptors have an enormous flexibility due to seven genes (NR1, NR2A-D and NR3A-B), alternative splicing, RNA-editing and extensive posttranslational modifications, like phosphorylation and glycosylation. NMDA receptors are thought to be responsible for excitotoxicity and subsequent downstream events like neuroinflammation and apoptosis and thus have been implicated in many important human pathologies, ranging from amyotrophic lateral sclerosis, Alzheimers and Parkinson disease, depression, epilepsy, trauma and stroke to schizophrenia. This fundamental significance of NMDA receptor-related excitotoxicity is discussed in the context of the developing clinical success of Memantine, but moreover set into relation to various proteomic and genetic markers of said diseases. The very complex localisational and functional regulation of NMDA receptors appears to be dependent on neuregulins and receptor tyrosine kinases in cholesterol-rich membrane domains (lipid rafts), calcium-related mitochondrial feedback-loops and subsynaptic structural elements like PSD-95 (post-synaptic density protein of 95 kD). The flexibility and multitude of interaction partners and possibilities of these highly dynamic molecular systems are discussed in terms of drug development strategies, in particular comparing high affinity and sub-type specific ligands to currently successful or promising therapies.
Keywords: NMDA receptor, neuregulin, cholesterol, excitotoxicity, neurodegeneration, dihydropyrimidinase-related protein 2, PARP-1, mitochondrial apoptotic pathway
Current Topics in Medicinal Chemistry
Title: NMDA Receptors are not Alone: Dynamic Regulation of NMDA Receptor Structure and Function by Neuregulins and Transient Cholesterol-Rich Membrane Domains Leads to Disease-Specific Nuances of Glutamate- Signalling
Volume: 6 Issue: 7
Author(s): Andre Schrattenholz and Vukic Soskic
Affiliation:
Keywords: NMDA receptor, neuregulin, cholesterol, excitotoxicity, neurodegeneration, dihydropyrimidinase-related protein 2, PARP-1, mitochondrial apoptotic pathway
Abstract: Glutamate receptors of the N-methyl-D-asparate (NMDA-) subtype are tetrameric allosteric and ligand-gated calcium channels. They are modulated by a variety of endogenous ligands and ions and play a pivotal role in memoryrelated signal transduction due to a voltage-dependent block by magnesium, which makes them Hebbian coincidence detectors. On the structural level NMDA receptors have an enormous flexibility due to seven genes (NR1, NR2A-D and NR3A-B), alternative splicing, RNA-editing and extensive posttranslational modifications, like phosphorylation and glycosylation. NMDA receptors are thought to be responsible for excitotoxicity and subsequent downstream events like neuroinflammation and apoptosis and thus have been implicated in many important human pathologies, ranging from amyotrophic lateral sclerosis, Alzheimers and Parkinson disease, depression, epilepsy, trauma and stroke to schizophrenia. This fundamental significance of NMDA receptor-related excitotoxicity is discussed in the context of the developing clinical success of Memantine, but moreover set into relation to various proteomic and genetic markers of said diseases. The very complex localisational and functional regulation of NMDA receptors appears to be dependent on neuregulins and receptor tyrosine kinases in cholesterol-rich membrane domains (lipid rafts), calcium-related mitochondrial feedback-loops and subsynaptic structural elements like PSD-95 (post-synaptic density protein of 95 kD). The flexibility and multitude of interaction partners and possibilities of these highly dynamic molecular systems are discussed in terms of drug development strategies, in particular comparing high affinity and sub-type specific ligands to currently successful or promising therapies.
Export Options
About this article
Cite this article as:
Schrattenholz Andre and Soskic Vukic, NMDA Receptors are not Alone: Dynamic Regulation of NMDA Receptor Structure and Function by Neuregulins and Transient Cholesterol-Rich Membrane Domains Leads to Disease-Specific Nuances of Glutamate- Signalling, Current Topics in Medicinal Chemistry 2006; 6 (7) . https://dx.doi.org/10.2174/156802606776894519
DOI https://dx.doi.org/10.2174/156802606776894519 |
Print ISSN 1568-0266 |
Publisher Name Bentham Science Publisher |
Online ISSN 1873-4294 |
Call for Papers in Thematic Issues
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
Drug Discovery in the Age of Artificial Intelligence
In the age of artificial intelligence (AI), we have witnessed a significant boom in AI techniques for drug discovery. AI techniques are increasingly integrated and accelerating the drug discovery process. These developments have not only attracted the attention of academia and industry but also raised important questions regarding the selection ...read more
From Biodiversity to Chemical Diversity: Focus of Flavonoids
Flavonoids are the largest group of polyphenols, plant secondary metabolites arising from the essential aromatic amino acid phenylalanine (or more rarely from tyrosine) via the phenylpropanoid pathway. The flavan nucleus is the basic 15-carbon skeleton of flavonoids (C6-C3-C6), which consists of two phenyl rings (A and B) and a heterocyclic ...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
-
Current Developments of Coumarin Compounds in Medicinal Chemistry
Current Pharmaceutical Design MtDNA As a Cancer Marker: A Finally Closed Chapter?
Current Genomics SPECT Radiopharmaceuticals for Dementia
Current Radiopharmaceuticals Potential Beneficial Effects of Marine Peptide on Human Neuron Health
Current Protein & Peptide Science Drugs of Abuse and their Detection Methodologies: Contribution of Chemical Sensor
Current Organic Chemistry Synthesis and First Evaluation of [<sup>18</sup>F]Fluorocyano- and [<sup>18</sup>F]Fluoronitroquinoxalinedione as Putative AMPA Receptor Antagonists
Medicinal Chemistry Pregabalin Dependence: A Case Report
Current Drug Safety Immunomodulatory Effects of Medicinal Plants used for Vitiligo in Traditional Persian Medicine
Current Drug Discovery Technologies Carbon Nano Tubes: Novel Drug Delivery System in Amelioration of Alzheimer’s Disease
Combinatorial Chemistry & High Throughput Screening Histamine H3 Antagonists for Treatment of Cognitive Deficits in CNS Diseases
Current Topics in Medicinal Chemistry Tissue Distribution and Pharmacodynamics: A Complicated Relationship
Current Drug Metabolism Antiobesity Carbonic Anhydrase Inhibitors
Current Topics in Medicinal Chemistry Delineating Somatostatins Neuronal Actions
Current Drug Targets - CNS & Neurological Disorders High Dose Zolpidem Induced Fetal Neural Tube Defects
Current Drug Safety ABC Transporters in the Development of Multidrug Resistance in Cancer Therapy
Current Pharmaceutical Design Strategy for a Genetic Assessment of Antipsychotic and Antidepressant- Related Proarrhythmia
Current Medicinal Chemistry R-Type Voltage-Gated Ca<sup>2+</sup> Channels in Cardiac and Neuronal Rhythmogenesis
Current Molecular Pharmacology Diazenyl Derivatives as Therapeutic and Diagnostic Agents Acting on Central Nervous System
Central Nervous System Agents in Medicinal Chemistry Ion Channel Modulation as a Therapeutic Approach in Multiple Sclerosis
Current Medicinal Chemistry The Pathophysiological Basis of Carotid Baroreceptor Stimulation for the Treatment of Resistant Hypertension
Current Vascular Pharmacology