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 language | English (US) |
|---|---|
| Pages (from-to) | 1444-1454 |
| Number of pages | 11 |
| Journal | Chemical Research in Toxicology |
| Volume | 26 |
| Issue number | 10 |
| DOIs | |
| State | Published - 2013 |
| Externally published | Yes |
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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 journal › Article
}
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 -