Glycine receptors : structure, function, and therapeutic implications

Abstract

Glycine receptors are considered as an integral part of higher brain function in mammals. The main function of glycine receptor is fast inhibitory transmission brought about by glycine neurotransmitter, its full agonist. This receptor is part of the glycinergic system which controls key physiological functions such as motor coordination, regulation of the rhythm of respiration and pain signalling. Glycine, a non-essential amino acid, causes hyperpolarisation within the glycine receptor, leading this ion channel to open and allow influx of chloride ion. The glycine receptor is found within the central nervous system and peripheral nervous system. It has also been found within amacrine cells, as well as renal medulla and cortex. The glycine receptor is a pentameric ligand-gated channel, part of the Cys-loop superfamily. It is composed of large ECD, C terminus, transmembrane domain M1-M4, and a 4α:1β glycine receptor subunit stoichiometry. The glycine receptor can be found as either homomeric or heteromeric subtypes. Alpha subtypes are crucial for important physiological functions such as breathing control and nociceptive system processing while the beta subunit aids in glycine receptor clustering and synapse stabilisation with its interaction with gephyrin scaffold protein. When hyperpolarised, the receptor transitions between close, open, and desensitised states. Factors that affect the activity and function of glycine receptors are gephyrin, ivermectin, strychnine and picrotoxin while certain endogenous modulators include partial agonists, positive allosteric modulator, antagonists, and bidirectional modulator are used for pharmacological modulation. Further studies need to be carried out on how glycine receptors are also implicated in chronic pain and nociception, epilepsy, autoimmune diseases and hyperekplexia.