IDENTIFICATION OF INTRACELLULAR AND EXTRACELLULAR DOMAINS MEDIATING SIGNAL-TRANSDUCTION IN THE INHIBITORY GLYCINE RECEPTOR CHLORIDE CHANNEL

Fast synaptic neurotransmission is mediated by transmitter-activated c onformational changes in ligand-gated ion channel receptors, culminati ng in opening of the integral ion channel pore. Human hereditary hyper ekplexia, or startle disease, is caused by mutations in both the intra cellular or extracellular loops flanking the pore-lining M2 domain of the glycine receptor alpha 1 subunit. These flanking domains are desig nated the M1-M2 loop and the M2-M3 loop respectively. We show that fou r startle disease mutations and six additional alanine substitution mu tations distributed throughout both loops result in uncoupling of the ligand binding sites from the channel activation gate. We therefore co nclude that the M1-M2 and M2-M3 loops act in parallel to activate the channel. Their locations strongly suggest that they act as hinges gove rning allosteric control of the M2 domain. As the members of the ligan d-gated ion channel superfamily share a common structure, this signal transduction model may apply to all members of this superfamily.