INSIGHTS INTO GLYCINE RECEPTOR STRUCTURE AND FUNCTION FROM STARTLE DISEASE MUTATIONS

Joseph W. Lynch, Department of Physiology and Pharmacology, School of Biomedical Sciences, University of Queensland, Brisbane, 4072. Australia.

Human hereditary hyperekplexia, or startle disease, is a rare neurological disorder characterised by an exaggerated response to unexpected stimuli. The response is typically accompanied by temporary but complete muscular rigidity often resulting in an unprotected fall. Symptoms of this disease are present from birth, with infants also displaying a severe hypertonia that gradually subsides throughout the first year of life. The disorder is successfully treated by benzodiazepines. Startle disease is caused by heritable missense mutations that disrupt the function of the glycine receptor chloride channel (GlyR). Since this receptor mediates inhibitory neurotransmission in the spinal cord, the mutations reduce the capacity of spinal cord reflex inhibitory circuits to dampen strong excitatory commands.

The GlyR is a member of the ligand-gated ion channel (LGIC) family, which includes the nicotonic acetylcholine and GABA_A receptors. GlyRs in vivo comprise both α and β subunits. The first-identified mutations were found on the α subunit M1-M2 and M2-M3 loops, which flank the M2 pore-lining domain. Analysis of these mutations revealed a crucial role for these domains in transmitting the ligand binding signal from the binding site to the activation gate. In addition, the M1-M2 loop mutations strongly affected receptor desensitisation and thus provide a starting point for understanding the molecular structural basis for this important function. More recently, a β subunit mutation has been identified that affects receptor sensitivity to glycine, thus revealing a hither-to unsuspected role for β subunits in ligand binding. These and other startle disease mutations are revealing important insights into the structure and function of the GlyR and other members of the LGIC family.