Allosteric modulation of glycine receptors

Abstract

Inhibitory (or strychnine sensitive) glycine receptors (GlyRs) are anion-selective transmitter-gated ion channels of the cys-loop superfamily, which includes among others also the inhibitory γ-aminobutyric acid receptors (GABA(A) receptors). While GABA mediates fast inhibitory neurotransmission throughout the CNS, the action of glycine as a fast inhibitory neurotransmitter is more restricted. This probably explains why GABA(A) receptors constitute a group of extremely successful drug targets in the treatment of a wide variety of CNS diseases, including anxiety, sleep disorders and epilepsy, while drugs specifically targeting GlyRs are virtually lacking. However, the spatially more restricted distribution of glycinergic inhibition may be advantageous in situations when a more localized enhancement of inhibition is sought. Inhibitory GlyRs are particularly relevant for the control of excitability in the mammalian spinal cord, brain stem and a few selected brain areas, such as the cerebellum and the retina. At these sites, GlyRs regulate important physiological functions, including respiratory rhythms, motor control, muscle tone and sensory as well as pain processing. In the hippocampus, RNA-edited high affinity extrasynaptic GlyRs may contribute to the pathology of temporal lobe epilepsy. Although specific modulators have not yet been identified, GlyRs still possess sites for allosteric modulation by a number of structurally diverse molecules, including alcohols, neurosteroids, cannabinoids, tropeines, general anaesthetics, certain neurotransmitters and cations. This review summarizes the present knowledge about this modulation and the molecular bases of the interactions involved.

Figure 1

Allosteric modulation of GlyR subtypes. The scheme summarizes the interactions between several groups of allosteric modulators with different GlyR subtypes. Examples of some representative chemical structures for each group of compounds are shown.

Figure 2

Molecular sites for positive allosteric modulators of GlyR function. Critical residues are shown for several allosteric modulators that exert positive effects on GlyR function. The amino acid positions described were identified in functional experiments performed on the α1-GlyR mutants. The molecular sites involved in the effects elicited by neuroactive steroids, some cannabinoid ligands (i.e. endocannabinoids and synthetic cannabinoids) and glutamate receptor ligands remain to be defined. Data are from Mascia et al. (1996b), Mihic et al. (1997), Laube et al. (2000), Lynch et al. (1998), Maksay et al. (2009), Lynagh and Lynch (2010), Xiong et al. (2011) and Yevenes et al. (2008).