tx400167b_si_001.pdf (1.58 MB)
Identification of a Possible Secondary Picrotoxin-Binding Site on the GABAA Receptor
journal contribution
posted on 2013-10-21, 00:00 authored by Timothy
S. Carpenter, Edmond Y. Lau, Felice C. LightstoneThe type A GABA receptors (GABARs)
are ligand-gated ion channels
(LGICs) found in the brain and are the major inhibitory neurotransmitter
receptors. Upon binding of an agonist, the GABAR opens and increases
the intraneuronal concentration of chloride ions, thus hyperpolarizing
the cell and inhibiting the transmission of the nerve action potential.
GABARs also contain many other
modulatory binding pockets that differ from the agonist-binding site.
The composition of the GABAR subunits can alter the properties of
these modulatory sites. Picrotoxin is a noncompetitive antagonist
for LGICs, and by inhibiting GABAR, picrotoxin can cause overstimulation
and induce convulsions. We use addition of picrotoxin to probe the
characteristics and possible mechanism of an additional modulatory
pocket located at the interface between the ligand-binding domain
and the transmembrane domain of the GABAR. Picrotoxin is widely regarded
as a pore-blocking agent that acts at the cytoplasmic end of the channel.
However, there are also data to suggest that there may be an additional,
secondary binding site for picrotoxin. Through homology modeling,
molecular docking, and molecular dynamics simulations, we show that
binding of picrotoxin to this interface pocket correlates with these
data, and negative modulation occurs at the pocket via a kinking of
the pore-lining helices into a more closed orientation.
History
Usage metrics
Categories
Keywords
cytoplasmic endGABA receptorsmodulatory pocketmodulatory siteshomology modelinguse additiontransmembrane domainpicrotoxinchloride ionsintraneuronal concentrationGABAA ReceptorThe typebinding siteGABAR subunitsmodulatory binding pocketsinterface pocket correlatesnerve actionLGICdynamics simulationsneurotransmitter receptors
Licence
Exports
RefWorks
BibTeX
Ref. manager
Endnote
DataCite
NLM
DC