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Towards an understanding of allosteric modulation of GABA-A receptor isoforms

Applicant Sigel Erwin
Number 156929
Funding scheme Project funding (Div. I-III)
Research institution Institut für Biochemie und Molekulare Medizin Universität Bern
Institution of higher education University of Berne - BE
Main discipline Biochemistry
Start/End 01.10.2014 - 31.07.2017
Approved amount 397'145.00
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All Disciplines (2)

Discipline
Biochemistry
Pharmacology, Pharmacy

Keywords (7)

electrophysiology; Benzodiazepine; receptor subtypes; virtual screening; GABA; GABA-A Receptor; photo-pharmacology

Lay Summary (German)

Lead
Unser Wachbefinden unterliegt einem subtilen Gleichgewicht von neuronaler Hemmung und Erregung. Die Familie der GABAA Rezeptoren ist der wichtigste Mediator der Hemmung. Benzodiazepine stimulieren diese Hemmung. Das Projekt soll zum Verständnis dieser Wirkung und der Rezeptordiversität beitragen.
Lay summary

Inhalt und Ziele des Forschungsprojekts

Ein Mitglied der GABAA Rezeptorfamilie kann durch Liganden der Benzodiazepinbindungsstelle stark, schwach oder gar nicht stimuliert warden. Verschiedene Mitglieder der Familie werden durch verschiedene Liganden stimuliert. Unsere Untersuchungen sollen die Grundlage für ein besseres Verständnis der strukturellen Eigenschaften liefern, welche hinter diesen Unterschieden stehen.

 

Wissenschaftlicher und gesellschaftlicher Kontext des Forschungsprojekts

Das Projekt befasst sich mit Grundlagenforschung. Ziel ist die Entwicklung von Grundlagen welche die Entwicklung neuer Medikamente erleichtern sollen. Diese Wirkstoffe sollten die Funktion einzelner Mitglieder der GABAA Rezeptorfamilie modulieren.

 

 

Direct link to Lay Summary Last update: 26.09.2014

Responsible applicant and co-applicants

Employees

Collaboration

Group / person Country
Types of collaboration
Novartis Animal Health Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
Prof. C. Müller / Bonn Germany (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
Dr. M. Ernst / Vienna Austria (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
Dr. Fedurco Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
Dr. W. Schühly / Graz Austria (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication

Communication with the public

Communication Title Media Place Year
Talks/events/exhibitions Benzodiazepines German-speaking Switzerland 2016

Associated projects

Number Title Start Funding scheme
141913 Transporters of Trypanosoma brucei: Phylogeny - Physiology - Pharmacology 01.06.2013 Sinergia
132806 GABA-A receptors: Molecular analysis, function in liver and direct connection to the cannabinoid signaling system 01.10.2010 Project funding (Div. I-III)

Abstract

Towards an understanding of allosteric modulation of GABAA receptor isoforms1. SUMMARY OF THE RESEARCH PLAN GABAA receptors are the most important mediators of neuronal inhibition. The GABAA receptors are pentameric membrane proteins. Their allosteric modulation is poorly understood at a structural level. A variety of receptor isoforms exists and it is expected that isoform specific modulation of receptor activity will result at least partially in the separation of the multiple effects of the non-selective drugs that exist now. We have recently developed a new method to establish the structure of the ligand containing benzodiazepine-binding site in the conformation stabilized by positive allosteric modulators. It is planned to apply this method for benzodiazepine antagonists and make use of the results of the above study to progress towards receptor isoform specific compounds. This method seems superior to the use of crystallized protein structures alone. Therefore it is unlikely to become obsolete with the expected crystallization of mammalian GABAA receptors.Specific aims1) It is of interest to understand at a structural level allosteric modulation of GABAA receptors. Comparison of the pocket structures stabilized by antagonists and positive allosteric modulators will contribute to our understanding of this process. 2) We also want to identify novel lead compounds that act isoform specifically at benzodiazepine-binding site of the GABAA receptor with either a positive allosteric or antagonistic action. It would for example be very attractive to develop an anxiolytic drug without sedative side effects. An isoform-specific positive allosteric modulator is likely to achieve this. A specific antagonist taken in combination with a non-selective modulator would specifically prevent action at this isoform.3) As side projects we plan to identify novel modulators of GABAA receptors and develop new research tools and commercial agents in collaboration with chemists. Photo-pharmacology will ultimately provide new experimental tools for receptor modulation with high resolution in time and in space down to single synapses. Optimization of the structure of a recently found open channel blocker of the GABAA receptor may lead to the development of an insecticide.Keywords: GABAA receptor, GABA, benzodiazepine, Xenopus oocyte, transfection, protein expression, radioactive ligand binding assay, electrophysiology, ion channel, protein structure, pharmacology, photo-pharmacology, insecticide, proximity accelerated chemical coupling reactions, virtual screening.
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