Chapter 8 - The inhibitory glycine receptor as a model of hereditary channelopathies

Abstract

Inhibitory glycine receptors mediate synaptic transmission in the mammalian spinal cord and brain stem. They constitute a family of ligand-gated chloride channels encoded by homologus subunit genes. Glycine receptor dysfunction is a candidate mechanism of hypertonic motor disorders in humans and animals. The human disease hyperekplexia is a congenital motor disorder that displays dominant and recessive modes of inheritance. This chapter describes glycine receptor genetics, protein structure and function, and it role in human and murine motor disorders. Analysis of protein and gene structure of individual ligand-gated ion channels reveals a homology between neurotransmitter receptors of entirely different pharmacology, on one hand and also for the same receptor in different species, on the other hand. The common features of inhibitory glycine receptor include: pentameric receptors; each subunit of size 50kDa; large N-terminus and four transmembrane (TM) segments as topology of subunits; TM2 forming the inner lining of channel pore; and a ring of charged amino acids at the extracellular end of the pore that conveys ion selectivity of the receptor. These receptors have four different α-subunits and one β-subunit. The functions of the glycine receptors are: ligand binding, signal transduction, gating, pore characterization, and functional modifications. The chapter briefly describes the glycine receptor defects i.e. hyperekplexia. This is caused by mutant alleles of the glycine receptor α- and β- subunit genes. The common symptoms include an exaggerated startle response to acoustic and tactile stimuli as well as episodic muscle stiffness.