Native glycine receptor subtypes and their physiological roles

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 pre-synaptically, where they modulate neurotransmitter release. Functional GlyRs are formed from a total of five subunits (a1 – a4, b). Although a subunits efficiently form homomeric GlyRs in recombinant expression systems, homomeric a1, a3 and a4 GlyRs are weakly expressed in adult neurons. In contrast, a2 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 a1b GlyRs. Immunocytochemical co-localisation experiments suggest the presence of a2b, a3b and a4b GlyRs at synapses in the adult mouse retina. Immunocytochemical and electrophysiological evidence also implicates a3b 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 b subunitcontaining 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.