Cyclothiazide potently inhibits γ-aminobutyric acid type A receptors in addition to enhancing glutamate responses

Lunbin Deng, Gong Chen

Research output: Contribution to journalArticle

40 Citations (Scopus)

Abstract

Ionotropic glutamate and γ-aminobutyric acid type A (GABA A) receptors mediate critical excitatory and inhibitory actions in the brain. Cyclothiazide (CTZ) is well known for its effect of enhancing glutamatergic transmission and is widely used as a blocker for α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA)-type glutamate receptor desensitization. Here, we report that in addition to its action on AMPA receptors, CTZ also exerts a powerful but opposite effect on GABAA receptors. We found that CTZ reversibly inhibited both evoked and spontaneous inhibitory postsynaptic currents, as well as GABA application-induced membrane currents, in a dose-dependent manner. Single-channel analyses revealed further that CTZ greatly reduced the open probability of GABAA receptor channels. These results demonstrate that CTZ interacts with both glutamate and GABAA receptors and shifts the excitation-inhibition balance in the brain by two independent mechanisms. Understanding the molecular mechanism of this double-faceted drug-receptor interaction may help in designing new therapies for neurological diseases.

Original languageEnglish (US)
Pages (from-to)13025-13029
Number of pages5
JournalProceedings of the National Academy of Sciences of the United States of America
Volume100
Issue number22
DOIs
StatePublished - Oct 28 2003

Fingerprint

Aminobutyrates
Glutamic Acid
GABA-A Receptors
AMPA Receptors
Glutamate Receptors
Drug Receptors
Inhibitory Postsynaptic Potentials
Brain
Drug Interactions
gamma-Aminobutyric Acid
cyclothiazide
Acids
Membranes

All Science Journal Classification (ASJC) codes

  • General

Cite this

@article{5f8a1850209d43f3b72216fb7088f463,
title = "Cyclothiazide potently inhibits γ-aminobutyric acid type A receptors in addition to enhancing glutamate responses",
abstract = "Ionotropic glutamate and γ-aminobutyric acid type A (GABA A) receptors mediate critical excitatory and inhibitory actions in the brain. Cyclothiazide (CTZ) is well known for its effect of enhancing glutamatergic transmission and is widely used as a blocker for α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA)-type glutamate receptor desensitization. Here, we report that in addition to its action on AMPA receptors, CTZ also exerts a powerful but opposite effect on GABAA receptors. We found that CTZ reversibly inhibited both evoked and spontaneous inhibitory postsynaptic currents, as well as GABA application-induced membrane currents, in a dose-dependent manner. Single-channel analyses revealed further that CTZ greatly reduced the open probability of GABAA receptor channels. These results demonstrate that CTZ interacts with both glutamate and GABAA receptors and shifts the excitation-inhibition balance in the brain by two independent mechanisms. Understanding the molecular mechanism of this double-faceted drug-receptor interaction may help in designing new therapies for neurological diseases.",
author = "Lunbin Deng and Gong Chen",
year = "2003",
month = "10",
day = "28",
doi = "10.1073/pnas.2133370100",
language = "English (US)",
volume = "100",
pages = "13025--13029",
journal = "Proceedings of the National Academy of Sciences of the United States of America",
issn = "0027-8424",
number = "22",

}

TY - JOUR

T1 - Cyclothiazide potently inhibits γ-aminobutyric acid type A receptors in addition to enhancing glutamate responses

AU - Deng, Lunbin

AU - Chen, Gong

PY - 2003/10/28

Y1 - 2003/10/28

N2 - Ionotropic glutamate and γ-aminobutyric acid type A (GABA A) receptors mediate critical excitatory and inhibitory actions in the brain. Cyclothiazide (CTZ) is well known for its effect of enhancing glutamatergic transmission and is widely used as a blocker for α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA)-type glutamate receptor desensitization. Here, we report that in addition to its action on AMPA receptors, CTZ also exerts a powerful but opposite effect on GABAA receptors. We found that CTZ reversibly inhibited both evoked and spontaneous inhibitory postsynaptic currents, as well as GABA application-induced membrane currents, in a dose-dependent manner. Single-channel analyses revealed further that CTZ greatly reduced the open probability of GABAA receptor channels. These results demonstrate that CTZ interacts with both glutamate and GABAA receptors and shifts the excitation-inhibition balance in the brain by two independent mechanisms. Understanding the molecular mechanism of this double-faceted drug-receptor interaction may help in designing new therapies for neurological diseases.

AB - Ionotropic glutamate and γ-aminobutyric acid type A (GABA A) receptors mediate critical excitatory and inhibitory actions in the brain. Cyclothiazide (CTZ) is well known for its effect of enhancing glutamatergic transmission and is widely used as a blocker for α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA)-type glutamate receptor desensitization. Here, we report that in addition to its action on AMPA receptors, CTZ also exerts a powerful but opposite effect on GABAA receptors. We found that CTZ reversibly inhibited both evoked and spontaneous inhibitory postsynaptic currents, as well as GABA application-induced membrane currents, in a dose-dependent manner. Single-channel analyses revealed further that CTZ greatly reduced the open probability of GABAA receptor channels. These results demonstrate that CTZ interacts with both glutamate and GABAA receptors and shifts the excitation-inhibition balance in the brain by two independent mechanisms. Understanding the molecular mechanism of this double-faceted drug-receptor interaction may help in designing new therapies for neurological diseases.

UR - http://www.scopus.com/inward/record.url?scp=0242363125&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=0242363125&partnerID=8YFLogxK

U2 - 10.1073/pnas.2133370100

DO - 10.1073/pnas.2133370100

M3 - Article

C2 - 14534329

AN - SCOPUS:0242363125

VL - 100

SP - 13025

EP - 13029

JO - Proceedings of the National Academy of Sciences of the United States of America

JF - Proceedings of the National Academy of Sciences of the United States of America

SN - 0027-8424

IS - 22

ER -