Ionotropic neurotransmitter receptors: activation and allosteric modulation
© Maksay and Fodor; licensee BioMed Central Ltd. 2007
Published: 14 November 2007
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.
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.
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.
Some of these allosteric modulators have nanomolar potencies and serve as promising leads for subunit-selective modulation of ionotropic receptors.
Support: OTKA K-62203.
This article is published under license to BioMed Central Ltd.