Identification of novel specific allosteric modulators of the glycine receptor using phage display.
The glycine receptor (GlyR) is a member of the Cys-loop superfamily of ligand-gated ion channels and the major mediator of inhibitory neurotransmission in the spinal cord and brainstem. Many allosteric modulators affect the functioning of members of this superfamily, with some such as benzodiazepines showing great specificity and others such as zinc, alcohols, and volatile anesthetics acting on multiple members. To date, no potent and efficacious allosteric modulator acting specifically at the GlyR has been identified, hindering both experimental characterization of the receptor and development of GlyR-related therapeutics. We used phage display to identify novel peptides that specifically modulate GlyR function. Peptide D12-116 markedly enhanced GlyR currents at low micromolar concentrations but had no effects on the closely related gamma-aminobutyric acid type A receptors. This approach can readily be adapted for use with other channels that currently lack specific allosteric modulators.
Tipps
Megan E
ME
Section of Neurobiology, University of Texas, A4800, 2500 Speedway, MBB 1.148, Austin, TX 78712, USA.
Lawshe
Jessica E
JE
Ellington
Andrew D
AD
Mihic
S John
SJ
D000494:Allosteric Regulation / Q000187:drug effects; D000595:Amino Acid Sequence; D002460:Cell Line; D055724:Electrophysiological Phenomena; D006801:Humans; D019151:Peptide Library; D010455:Peptides / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D018009:Receptors, Glycine / Q000378:metabolism*; D013379:Substrate Specificity
D019151:Peptide Library; D010455:Peptides; D018009:Receptors, Glycine