Structure, Diversity, Pharmacology, and Pathology of Glycine Receptor Chloride Channels

Glycine, the simplest of all amino acids, is highly enriched in spinal cord and brain stem compared with other regions of the central nervous system. Classical physiological analysis has revealed that glycine serves as a major inhibitory neurotransmitter in the control of motor and sensory pathways (APRISON 1990). In the nerve terminals of glycinergic interneurons in spinal cord and brain stem, cytosolic glycine is concentrated in small clear synaptic vesicles by an H+-dependent vesicular transporter. Excitation of the interneurons causes Ca2+-triggered fusion of these synaptic vesicles with the presynaptic plasma membrane, thus initiating glycine release into the synaptic cleft. This results in the activation of postsynaptic glycine receptors (GlyRs) which mediate an increase in chloride conductance by opening an integral anion channel in response to agonist binding. As the chloride equilibrium of mature neurons is close to their resting potential, glycine-mediated Cl-influx normally antagonizes depolarization by Na+ influx and thus inhibits the propagation of action potentials. However, glycine can also serve as an excitatory neurotransmitter. Immature neurons in the developing central nervous system often contain very high intracellular chloride concentrations (WANG et al. 1994). In these neurons, glycine-induced increases in chloride conductance cause Cl-efflux, resulting in membrane depolarization and neurotransmitter release (REICHLING et al.1994; BOEHM et al.1997). Excitatory GlyRs may be especially relevant to synaptogenesis, since glycine-triggered rises in intracellular Ca2+ have recently been shown to be crucial for the correct formation of postsynaptic glycinergic membrane specializations (KIRSCH and BETZ 1998). Thus, the developmental regulation of intracellular Cl-oncentration critically controls the nature of the postsynaptic response to glycine