Glycine and its synaptic interactions

Glycine is a major neurotransmitter of inhibitory neurons in the spinal cord and brainstem. In many of these neurons, glycine coexists with γ-aminobutyric acid (GABA). The synaptic availability of glycine is controlled by 2 different transporters, and its postsynaptic effects are mediated by a specific chloride (Cl⁻) channel receptor. In the adult nervous system, glycine exerts fast postsynaptic inhibition that is important for control of excitability of motor neurons, auditory processing, pain transmission in the dorsal horn, and other functions. Corelease of GABA may affect the temporal profile of the postsynaptic effects of glycine. Glycine is also a coagonist of glutamate on NMDA receptors (NMDARs). Studies in vitro and in knockout mouse models have provided insight on the complex synaptic interactions among glycine, GABA, and glutamate, and on the consequences of impaired regulation of glycinergic transmission in the nervous system. Excessive synaptic levels of glycine may explain the manifestations of nonketotic hyperglycinemia, whereas loss-of-function mutations impairing glycinergic signaling have been linked to familial hyperekplexia. Autoimmune disorders affecting the glycine receptor (GlyR) complex may also result in excessive motoneuron excitability. Pharmacologic blockade of a glycine transporter may constitute a novel approach to increase NMDAR activity in schizophrenia. Many of these topics have been recently reviewed.^1,–,9