Native glycine receptor subtypes and their physiological roles

Abstract

The glycine receptor chloride channel (GlyR), a member of the pentameric Cys-loop ion channel receptor family, mediates inhibitory neurotransmission in the spinal cord, brainstem and retina. They are also found presynaptically, where they modulate neurotransmitter release. Functional GlyRs are formed from a total of five subunits (alpha1-alpha4, beta). Although alpha subunits efficiently form homomeric GlyRs in recombinant expression systems, homomeric alpha1, alpha3 and alpha4 GlyRs are weakly expressed in adult neurons. In contrast, alpha2 homomeric GlyRs are abundantly expressed in embryonic neurons, although their numbers decline sharply by adulthood. Numerous lines of biochemical, biophysical, pharmacological and genetic evidence suggest the majority of glycinergic neurotransmission in adults is mediated by heteromeric alpha1beta GlyRs. Immunocytochemical co-localisation experiments suggest the presence of alpha2beta, alpha3beta and alpha4beta GlyRs at synapses in the adult mouse retina. Immunocytochemical and electrophysiological evidence also implicates alpha3beta GlyRs as important mediators of glycinergic inhibitory neurotransmission in nociceptive sensory neuronal circuits in peripheral laminae of the spinal cord dorsal horn. It is yet to be determined why multiple GlyR synaptic subtypes are differentially distributed in these and possibly other locations. The development of pharmacological agents that can discriminate strongly between different beta subunit-containing GlyR isoforms will help to address this issue, and thereby provide important insights into a variety of central nervous system functions including retinal signal processing and spinal pain mechanisms. Finally, agents that selectively potentiate different GlyR isoforms may be useful as therapeutic lead compounds for peripheral inflammatory pain and movement disorders such as spasticity.

Ethanol Reduces Neuronal Excitability of Lateral Orbitofrontal Cortex Neurons Via a Glycine Receptor Dependent Mechanism

“…In a recent study, PCR analysis revealed that GlyRa2 subunits dominate over a1 and a3 in frontal cortex, striatum and hippocampus in young animals and this profile is maintained in adulthood despite significant reductions in the overall expression of all subunits (Jonsson et al, 2012). A similar finding was reported for neurons in the basolateral amygdala (McCool and Farroni, 2001) suggesting that while a1 GlyRs are the dominant subtype in adult spinal cord (Lynch, 2009), a2 containing GlyRs may generate a significant population of functional neuronal GlyRs in higher brain areas. This conclusion is supported by findings from a recent study showing that dissociated rat PFC neurons generate robust glycine-activated currents that are strychnine-sensitive and exhibit an age-dependent change in picrotoxin sensitivity suggesting a loss of GlyRb subunits (Lu and Ye, 2011).…”

Tranexamic acid–associated seizures: Causes and treatment

“…We found that TXA acts as a competitive antagonist of glycine receptors, with an IC 50 of 1mM (see Fig 2B) 47. Similar to GABA A receptors, glycine receptors generate both synaptic currents and tonic inhibitory currents (Fig 3A) 61. Thus, we compared the potency of TXA for inhibition of spontaneous miniature inhibitory postsynaptic currents and a tonic current in spinal cord neurons (see Fig 3C) 47.…”

Insight in nAChR subtype selectivity from AChBP crystal structures

“…GABA A receptors are modulated by anesthetics or by compounds such as benzodiazepines to treat sleep or mood disturbances [6]. Glycine receptors, involved in sensory signal processing, are potential drug targets for relieving peripheral inflammatory pain or spastic conditions [7,8]. A common aspect of neurotransmitter binding is that it takes place at the subunit interfaces of the extracellular LBD whereas the transmembrane regions form the ion channel and constitute the ion selectivity filters.…”