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A System for Assessing Dual Action Modulators of Glycine Transporters and Glycine Receptors

School of Medical Sciences, University of Sydney, Sydney, NSW 2006, Australia
School of Mathematical and Physical Sciences, University of Technology Sydney, Sydney, NSW 2007, Australia
Author to whom correspondence should be addressed.
Biomolecules 2020, 10(12), 1618;
Received: 23 October 2020 / Revised: 23 November 2020 / Accepted: 25 November 2020 / Published: 30 November 2020
(This article belongs to the Special Issue Glycine Transporters and Receptors as Targets for Analgesics)
Reduced inhibitory glycinergic neurotransmission is implicated in a number of neurological conditions such as neuropathic pain, schizophrenia, epilepsy and hyperekplexia. Restoring glycinergic signalling may be an effective method of treating these pathologies. Glycine transporters (GlyTs) control synaptic and extra-synaptic glycine concentrations and slowing the reuptake of glycine using specific GlyT inhibitors will increase glycine extracellular concentrations and increase glycine receptor (GlyR) activation. Glycinergic neurotransmission can also be improved through positive allosteric modulation (PAM) of GlyRs. Despite efforts to manipulate this synapse, no therapeutics currently target it. We propose that dual action modulators of both GlyTs and GlyRs may show greater therapeutic potential than those targeting individual proteins. To show this, we have characterized a co-expression system in Xenopus laevis oocytes consisting of GlyT1 or GlyT2 co-expressed with GlyRα1. We use two electrode voltage clamp recording techniques to measure the impact of GlyTs on GlyRs and the effects of modulators of these proteins. We show that increases in GlyT density in close proximity to GlyRs diminish receptor currents. Reductions in GlyR mediated currents are not observed when non-transportable GlyR agonists are applied or when Na+ is not available. GlyTs reduce glycine concentrations across different concentration ranges, corresponding with their ion-coupling stoichiometry, and full receptor currents can be restored when GlyTs are blocked with selective inhibitors. We show that partial inhibition of GlyT2 and modest GlyRα1 potentiation using a dual action compound, is as useful in restoring GlyR currents as a full and potent single target GlyT2 inhibitor or single target GlyRα1 PAM. The co-expression system developed in this study will provide a robust means for assessing the likely impact of GlyR PAMs and GlyT inhibitors on glycine neurotransmission. View Full-Text
Keywords: glycine transporter; glycine receptor; analgesics; lipids glycine transporter; glycine receptor; analgesics; lipids
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MDPI and ACS Style

Sheipouri, D.; Gallagher, C.I.; Shimmon, S.; Rawling, T.; Vandenberg, R.J. A System for Assessing Dual Action Modulators of Glycine Transporters and Glycine Receptors. Biomolecules 2020, 10, 1618.

AMA Style

Sheipouri D, Gallagher CI, Shimmon S, Rawling T, Vandenberg RJ. A System for Assessing Dual Action Modulators of Glycine Transporters and Glycine Receptors. Biomolecules. 2020; 10(12):1618.

Chicago/Turabian Style

Sheipouri, Diba, Casey I. Gallagher, Susan Shimmon, Tristan Rawling, and Robert J. Vandenberg. 2020. "A System for Assessing Dual Action Modulators of Glycine Transporters and Glycine Receptors" Biomolecules 10, no. 12: 1618.

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