TY - JOUR
T1 - Direct channel-gating and modulatory effects of triiodothyronine on recombinant GABA(A) receptors
AU - Chapell, Richard
AU - Martin, Joseph
AU - MacHu, Tina K.
AU - Leidenheimer, Nancy J.
N1 - Funding Information:
The authors would like to thank Dr. Paul J. Whiting for generously providing the GABA A receptor subunit cDNAs. This work was supported by NINDS grant R29NS32131 and a grant from The Stiles Foundation to NJL and NSF grant IBN9412109 to JVM.
Copyright:
Copyright 2007 Elsevier B.V., All rights reserved.
PY - 1998/5/15
Y1 - 1998/5/15
N2 - We have previously shown that triiodothyronine (T3) inhibits γ- aminobutyric acid type A (GABA(A)) receptors in synaptoneurosomes and transfected cells. To further characterize this phenomenon, the effect of T3 on recombinant GABA(A) receptors expressed in Xenopus oocytes was investigated using the two-electrode voltage-clamp method. T3 inhibited GABA- gated chloride currents in a non-competitive manner and yielded an IC50 of 7.3 ± 0.8 μM in oocytes coexpressing α1 β2 γ(2L) receptor subunits. T3 had no inhibitory effect on α6 β2 γ(2L) or β2 γ(2L) receptor constructs, indicating that the α1 subunit imparts T3 sensitivity to the receptor. In addition to the inhibitory effect of T3 on GABA responses, T3 alone induced a current in oocytes expressing α1 β2 γ(2L), α6 β2 γ(2L) and β2 γ(2L) constructs. This current displayed a reversal potential identical to that of GABA-gated chloride currents, and was blocked by picrotoxin (10 μM), but not by bicuculline (50 μM), indicating that T3 gates the chloride channel by binding to a site other than the GABA-binding site. The direct channel-gating action of T3 was concentration-dependent, with an EC50 of 23 ± 5 μM. The actions of T3 are unique in that T3 acts as a noncompetitive antagonist in the presence of GABA but can directly gate the chloride channel in the absence of GABA.
AB - We have previously shown that triiodothyronine (T3) inhibits γ- aminobutyric acid type A (GABA(A)) receptors in synaptoneurosomes and transfected cells. To further characterize this phenomenon, the effect of T3 on recombinant GABA(A) receptors expressed in Xenopus oocytes was investigated using the two-electrode voltage-clamp method. T3 inhibited GABA- gated chloride currents in a non-competitive manner and yielded an IC50 of 7.3 ± 0.8 μM in oocytes coexpressing α1 β2 γ(2L) receptor subunits. T3 had no inhibitory effect on α6 β2 γ(2L) or β2 γ(2L) receptor constructs, indicating that the α1 subunit imparts T3 sensitivity to the receptor. In addition to the inhibitory effect of T3 on GABA responses, T3 alone induced a current in oocytes expressing α1 β2 γ(2L), α6 β2 γ(2L) and β2 γ(2L) constructs. This current displayed a reversal potential identical to that of GABA-gated chloride currents, and was blocked by picrotoxin (10 μM), but not by bicuculline (50 μM), indicating that T3 gates the chloride channel by binding to a site other than the GABA-binding site. The direct channel-gating action of T3 was concentration-dependent, with an EC50 of 23 ± 5 μM. The actions of T3 are unique in that T3 acts as a noncompetitive antagonist in the presence of GABA but can directly gate the chloride channel in the absence of GABA.
KW - GABA(A) receptor
KW - Triiodothyronine
KW - Two- electrode
KW - Voltage-clamp
KW - Xenopus oocyte
UR - http://www.scopus.com/inward/record.url?scp=0032524574&partnerID=8YFLogxK
U2 - 10.1016/S0014-2999(98)00182-4
DO - 10.1016/S0014-2999(98)00182-4
M3 - Article
C2 - 9669504
AN - SCOPUS:0032524574
VL - 349
SP - 115
EP - 121
JO - European Journal of Pharmacology
JF - European Journal of Pharmacology
SN - 0014-2999
IS - 1
ER -