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Ionotropic neurotransmitter receptors: activation and allosteric modulation

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.

Acknowledgements

Support: OTKA K-62203.

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Correspondence to Gábor Maksay.

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Open Access This article is published under license to BioMed Central Ltd. This is an Open Access article is distributed under the terms of the Creative Commons Attribution 2.0 International License (https://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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Maksay, G., Fodor, L. Ionotropic neurotransmitter receptors: activation and allosteric modulation. BMC Pharmacol 7, A37 (2007). https://doi.org/10.1186/1471-2210-7-S2-A37

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

Keywords

  • Cerebellar Granule Cell
  • Strychnine
  • Ionotropic Receptor
  • Mutation R271L
  • Major Inhibitory Neurotransmitter