Molecular Pharmacology of the Glycine Receptor Chloride Channel

Abstract

The glycine receptor (GlyR) Cl(-) channel belongs to the cysteine-loop family of ligand-gated ion channel receptors. It is best known for mediating inhibitory neurotransmission in motor and sensory reflex circuits of the spinal cord, although glycinergic synapses are also present in the brain stem, cerebellum and retina. Extrasynaptic GlyRs are widely distributed throughout the central nervous system and they are also found in sperm and macrophages. A total of 5 GlyR subunits (alpha1-4 and beta) have been identified. Embryonic receptors comprise alpha2 homomers whereas adult receptors comprise predominantly alpha beta heteromers in a 2:3 stoichiometry. Notably, the alpha3 subunit is present in synaptic GlyRs that mediate inhibitory neurotransmission onto spinal nociceptive neurons. These receptors are specifically inhibited by inflammatory mediators, implying a role for alpha3-containing GlyRs in inflammatory pain sensitisation. Because molecules that increase GlyR current may have clinical potential as muscle relaxant and peripheral analgesic drugs, this review focuses on the molecular pharmacology of GlyR potentiating substances. Of all GlyR potentiating substances identified to date, we conclude that 5HT(3)R antagonists such as tropisetron offer the most promise as therapeutic lead compounds. However, one problem is that that virtually all known GlyR potentiating compounds, including tropisetron analogues, lack specificity for the GlyR. Another is that almost nothing is known about the pharmacological properties of alpha3-containing GlyRs, which is the subtype of choice for targeting by novel antinociceptive agents. These issues need to be addressed before GlyR-specific therapeutics can be developed.

The role of glycine in regulated cell death

“…The inhibitory neuronal glycine receptor (GlyR) is a pentameric gated chloride channel composed of alpha and beta subunits [109,141]. It is a member of the nicotinoid receptor, cysteine-loop superfamily that also includes the excitatory nicotinic acetylcholine receptor, the inhibitory γ-aminobutyric acid, Type A receptors, and the cation permeable serotonin type 3 receptor.…”

“…D-serine is without significant activity [144]. Glycine is antagonized by low micromolar concentrations of strychnine, which binds to the α subunit [109,141]. In addition to being the primary agonist at the neuronal glycine receptor, glycine is a coagonist at the NMDA receptor [74].…”

“…It is a high affinity competitive antagonist that binds to the 48 kDa α subunit, inhibits all known GlyR isoforms and is considered to be the definitive pharmacological tool for identifying glycinergic synaptic currents [141] with an IC50 for inhibition of glycine induced chloride currents in hippocampal neurons of 20 nM and a maximal effect at 1 μM [144]. True glycine cytoprotection (as distinct from glycine effects on signaling in nonneuronal cells that will be addressed below) has never been shown to be antagonized by strychnine.…”

Effects of inhibitory amino acids on expression of GABAA Rα and glycine Rα1 in hypoxic rat cortical neurons during development

“…In humans, the composition of the pentamer changes from α2 subunits in the fetal CNS to α1- and β-subunits in the adult CNS. Embryonic receptors comprise α2 homomers whereas adult receptors comprise predominantly α- and β-heteromers in a 2:3 stoichiometry (Webb & Lynch, 2007). However, there is no direct evidence for the development of GlyRα1 in the cortical neurons.…”

“…The glycine-mediated inhibitory neurotransmission is essential for voluntary motor control and the reflex responses (Lynch, 2004; Webb & Lynch, 2007). Besides its inhibition of neurotransmission, glycine also regulates interneuron differentiation during development of the central neural network (McDearmid et al , 2006) and depresses neurite outgrowth by shunting the neuronal excitability (Tapia et al ., 2001).…”