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Identification of intracellular and extracellular domains mediating signal transduction in the inhibitory glycine receptor chloride channel
Author(s) -
Lynch Joseph W.,
Rajendra Sundran,
Pierce Kerrie D.,
Handford Cheryl A.,
Barry Peter H.,
Schofield Peter R.
Publication year - 1997
Publication title -
the embo journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 7.484
H-Index - 392
eISSN - 1460-2075
pISSN - 0261-4189
DOI - 10.1093/emboj/16.1.110
Subject(s) - biology , extracellular , signal transduction , chloride channel , intracellular , inhibitory postsynaptic potential , glycine receptor , microbiology and biotechnology , receptor , transduction (biophysics) , glycine , biochemistry , amino acid , neuroscience
Fast synaptic neurotransmission is mediated by transmitter‐activated conformational changes in ligand‐gated ion channel receptors, culminating in opening of the integral ion channel pore. Human hereditary hyperekplexia, or startle disease, is caused by mutations in both the intracellular or extracellular loops flanking the pore‐lining M2 domain of the glycine receptor α1 subunit. These flanking domains are designated the M1‐M2 loop and the M2‐M3 loop respectively. We show that four startle disease mutations and six additional alanine substitution mutations distributed throughout both loops result in uncoupling of the ligand binding sites from the channel activation gate. We therefore conclude that the M1‐M2 and M2‐M3 loops act in parallel to activate the channel. Their locations strongly suggest that they act as hinges governing allosteric control of the M2 domain. As the members of the ligand‐gated ion channel superfamily share a common structure, this signal transduction model may apply to all members of this superfamily.