Identification of a possible secondary picrotoxin-binding site on the GABAA receptor

Timothy S. Carpenter, Edmond Y Lau, Felice C Lightstone

Research output: Contribution to journalArticle

18 Citations (Scopus)

Abstract

The 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.

Original languageEnglish (US)
Pages (from-to)1444-1454
Number of pages11
JournalChemical Research in Toxicology
Volume26
Issue number10
DOIs
StatePublished - 2013
Externally publishedYes

Fingerprint

Picrotoxin
GABA-A Receptors
GABA Receptors
Binding Sites
Ligand-Gated Ion Channels
GABA Agonists
Neurotransmitter Receptor
Molecular modeling
Molecular Dynamics Simulation
Linings
Action Potentials
Molecular dynamics
Chlorides
Brain
Seizures
Modulation
Ions
Ligands
Computer simulation
Chemical analysis

ASJC Scopus subject areas

  • Toxicology

Cite this

Identification of a possible secondary picrotoxin-binding site on the GABAA receptor. / Carpenter, Timothy S.; Lau, Edmond Y; Lightstone, Felice C.

In: Chemical Research in Toxicology, Vol. 26, No. 10, 2013, p. 1444-1454.

Research output: Contribution to journalArticle

@article{ccbdf9954e9c4952b1ef361c7fd4cdcd,
title = "Identification of a possible secondary picrotoxin-binding site on the GABAA receptor",
abstract = "The 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.",
author = "Carpenter, {Timothy S.} and Lau, {Edmond Y} and Lightstone, {Felice C}",
year = "2013",
doi = "10.1021/tx400167b",
language = "English (US)",
volume = "26",
pages = "1444--1454",
journal = "Chemical Research in Toxicology",
issn = "0893-228X",
publisher = "American Chemical Society",
number = "10",

}

TY - JOUR

T1 - Identification of a possible secondary picrotoxin-binding site on the GABAA receptor

AU - Carpenter, Timothy S.

AU - Lau, Edmond Y

AU - Lightstone, Felice C

PY - 2013

Y1 - 2013

N2 - The 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.

AB - The 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.

UR - http://www.scopus.com/inward/record.url?scp=84886669732&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84886669732&partnerID=8YFLogxK

U2 - 10.1021/tx400167b

DO - 10.1021/tx400167b

M3 - Article

C2 - 24028067

AN - SCOPUS:84886669732

VL - 26

SP - 1444

EP - 1454

JO - Chemical Research in Toxicology

JF - Chemical Research in Toxicology

SN - 0893-228X

IS - 10

ER -