Abstract
Therapeutics designed to increase synaptic neurotransmitter levels by inhibiting neurotransmitter sodium symporters (NSSs) classify a strategic approach to treat brain disorders such as depression or epilepsy, however, the critical elementary steps that couple downhill flux of sodium to uphill transport of neurotransmitter are not distinguished as yet. Here we present modelling of NSS member neuronal GAT1 with the substrate γ-aminobutyric acid (GABA), the major inhibitory neurotransmitter. GABA binding is simulated with the occluded conformation of GAT1 homodimer in an explicit lipid/water environment. Simulations performed in the 1-10 ns range of time elucidated persistent formation of halfextended minor and H-bridged major GABA conformations, referred to as binding and traverse conformations, respectively. The traverse GABA conformation was further stabilized by GAT1-bound Na+(1). We also observed Na+(1) translocation to GAT1-bound Cl- as well as the appearance of water molecules at GABA and GAT1-bound Na+(2), conjecturing causality. Scaling dynamics suggest that the traverse GABA conformation may be valid for developing substrate inhibitors with high efficacy. The potential for this finding is significant with impact not only in pharmacology but wherever understanding of the mechanism of neurotransmitter uptake is valuable.
Keywords: Binding and traverse conformation, neurotransmitter sodium symporter family, neuronal GABA symporter subtype, sodium symport.
Current Drug Discovery Technologies
Title:Sodium-Assisted Formation of Binding and Traverse Conformations of the Substrate in a Neurotransmitter Sodium Symporter Model
Volume: 11 Issue: 3
Author(s): Agnes Simon, Akos Bencsura, Laszlo Heja, Csaba Magyar and Julianna Kardos
Affiliation:
Keywords: Binding and traverse conformation, neurotransmitter sodium symporter family, neuronal GABA symporter subtype, sodium symport.
Abstract: Therapeutics designed to increase synaptic neurotransmitter levels by inhibiting neurotransmitter sodium symporters (NSSs) classify a strategic approach to treat brain disorders such as depression or epilepsy, however, the critical elementary steps that couple downhill flux of sodium to uphill transport of neurotransmitter are not distinguished as yet. Here we present modelling of NSS member neuronal GAT1 with the substrate γ-aminobutyric acid (GABA), the major inhibitory neurotransmitter. GABA binding is simulated with the occluded conformation of GAT1 homodimer in an explicit lipid/water environment. Simulations performed in the 1-10 ns range of time elucidated persistent formation of halfextended minor and H-bridged major GABA conformations, referred to as binding and traverse conformations, respectively. The traverse GABA conformation was further stabilized by GAT1-bound Na+(1). We also observed Na+(1) translocation to GAT1-bound Cl- as well as the appearance of water molecules at GABA and GAT1-bound Na+(2), conjecturing causality. Scaling dynamics suggest that the traverse GABA conformation may be valid for developing substrate inhibitors with high efficacy. The potential for this finding is significant with impact not only in pharmacology but wherever understanding of the mechanism of neurotransmitter uptake is valuable.
Export Options
About this article
Cite this article as:
Simon Agnes, Bencsura Akos, Heja Laszlo, Magyar Csaba and Kardos Julianna, Sodium-Assisted Formation of Binding and Traverse Conformations of the Substrate in a Neurotransmitter Sodium Symporter Model, Current Drug Discovery Technologies 2014; 11 (3) . https://dx.doi.org/10.2174/1570163811666140812110735
DOI https://dx.doi.org/10.2174/1570163811666140812110735 |
Print ISSN 1570-1638 |
Publisher Name Bentham Science Publisher |
Online ISSN 1875-6220 |
- 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
-
The Role of Microglial Cells on Neuroinflammation: Possible Therapeutic Applications
Recent Patents on Regenerative Medicine Novel Pyrimidine based Semicarbazones: Confirmation of Four Binding Site Pharmacophoric Model Hypothesis for Antiepileptic Activity
Central Nervous System Agents in Medicinal Chemistry Altered Homeostatic Functions in Reactive Astrocytes and Their Potential as a Therapeutic Target After Brain Ischemic Injury
Current Pharmaceutical Design UGT1A1 Mediated Drug Interactions and its Clinical Relevance
Current Drug Metabolism Targeting Bacterial Metalloenzymes: A New Strategy for the Development of Anti-Infective Agents
Anti-Infective Agents in Medicinal Chemistry Meet the Editorial Board Member
CNS & Neurological Disorders - Drug Targets An Update on GABAρ Receptors
Current Neuropharmacology 1,2,4-Triazine Analogs as Novel Class of Therapeutic Agents
Mini-Reviews in Medicinal Chemistry Nutrition and Bone Health: Its Relationship to Osteoporosis
Current Nutrition & Food Science Elaboration and Validation of HPLC/DAD Method for Quality Control of Products Containing Cannabidiol
Current Pharmaceutical Analysis Bhasma: Indian Perspective of Nanomedicinal Technology
Recent Patents on Nanomedicine Assessment of Memory Impairment in Early Diagnosis of Alzheimer’s Disease
Current Alzheimer Research NMDA Receptor Pharmacology: Perspectives from Molecular Biology
Current Drug Targets subject Index To Volume 1
Current Drug Targets - CNS & Neurological Disorders Activators and Inhibitors of the Ion Channel of the NMDA Receptor
Current Drug Targets Synthesis and Pharmacological Screening of Novel 1,3-Disubstituted 5-Pyrazolones as Anticonvulsant Agents
Current Bioactive Compounds Efficient Synthesis of 5-Arylmethyl-5-phenylimidazolidine-2,4-dione (or 5-Arylmethyl-5-phenyl-2-thioxoimidazolidin-4-one) from Chalcone Oxides Under Ultrasound Irradiation
Letters in Organic Chemistry Neuropsychiatric Systemic Lupus Erythematosus
Current Neuropharmacology The Role of Adenosine in Alzheimers Disease
Current Neuropharmacology Anticonvulsant, Anxiolytic and Antidepressant Properties of the β-caryophyllene in Swiss Mice: Involvement of Benzodiazepine-GABAAergic, Serotonergic and Nitrergic Systems
Current Molecular Pharmacology