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Open Access

Ionotropic neurotransmitter receptors: activation and allosteric modulation

BMC Pharmacology20077(Suppl 2):A37

https://doi.org/10.1186/1471-2210-7-S2-A37

Published: 14 November 2007

Introduction

GABA and glycine are major inhibitory neurotransmitters. GABAA and glycine receptors (GlyR) form pentameric chloride channels and belong to the Cys-loop receptor superfamily with 5-HT3 serotonin and nicotinic receptors. Homology modelling has revealed distinctive binding interactions of antagonists and agonists in the interface of 5-HT3A receptors leading to ligand translocation, closure of the binding cavity and ionophore activation. Allosteric modulation of ionotropic receptors enables the pharmacological fine-tuning of neurotransmission.

Methods

Radioligand binding of [3H]EBOB and [3H]strychnine to native GABAA and recombinant GlyRs, respectively, and whole-cell patch clamp electrophysiology in cultured rat cerebellar granule cells.

Results

A 17β-alkenyl derivative of the neurosteroid allopregnanolone antagonized the potentiating effects of allopregnanolone selectively on a cerebellar (α6βδ) population of GABAA receptors with nanomolar potency. Nortropine esters exerted bidirectional allosteric modulation of GlyRs: nor-O-zatosetron had the highest affinity reported for GlyRs. The anaesthetic propofol restored the potency of glycine impaired by a point mutation R271L of GlyR α1 subunits leading to hyperekplexia, an inherited neurological disorder.

Conclusion

Some of these allosteric modulators have nanomolar potencies and serve as promising leads for subunit-selective modulation of ionotropic receptors.

Declarations

Acknowledgements

Support: OTKA K-62203.

Authors’ Affiliations

(1)
Department of Molecular Pharmacology, Institute of Biomolecular Chemistry, CRC-HAS
(2)
Department of Pharmacology, G. Richter Plc.

Copyright

© Maksay and Fodor; licensee BioMed Central Ltd. 2007

This article is published under license to BioMed Central Ltd.

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