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Kinetic analysis of evoked IPSCs discloses mechanism of antagonism of synaptic GABAA receptors by picrotoxin.

Abstract：

BACKGROUND AND PURPOSE:Although picrotoxin is a well-established antagonist of GABA(A) receptors, detailed studies of its action on inhibitory synaptic transmission have not previously been made. EXPERIMENTAL APPROACH:Electrophysiological techniques were used to study the action of picrotoxin on inhibitory postsynaptic currents (IPSCs) evoked in hippocampal neurones, in culture and slice preparations prepared from Wistar rat embryos and juveniles, respectively. KEY RESULTS:Picrotoxin gradually reduced the amplitude of GABA(A) receptor-mediated eIPSCs in a concentration-dependent manner. This was accompanied by a marked acceleration of the eIPSC decay kinetics, which, in contrast to the effect on amplitude, developed immediately and was completely reversed on washing. The decaying phase of the IPSC could be resolved into two components; 30 microM picrotoxin reduced tau(fast) by 34% and increased its relative amplitude, while tau(slow) was reduced by 38%, and its relative amplitude decreased. The area under the decaying phase of the normalized eIPSC showed an immediate reduction by 36% in 30 microM picrotoxin. With increasing concentrations of picrotoxin, this normalized area converged towards 55% of the control, indicating that the rate of relaxation and block has a finite maximum. This implies that picrotoxin does not act by a pore-occluding mechanism (open-channel blocking), and suggests allosteric stabilization of desensitized receptor states as a more likely alternative. This was corroborated by modelling, based on two established microscopic GABA(A) receptor transition schemes. CONCLUSIONS AND IMPLICATIONS:Although the identity of the stabilized state has not been determined unequivocally, picrotoxin effectively traps synaptic GABA(A) receptors in a desensitized state.

journal_name

Br J Pharmacol

journal_title

British journal of pharmacology

authors

Korshoej AR,Holm MM,Jensen K,Lambert JD

doi

10.1111/j.1476-5381.2009.00542.x

subject

Has Abstract

pub_date

2010-02-01 00:00:00

pages

636-49

issue

eissn

0007-1188

issn

1476-5381

pii

BPH542

journal_volume

159

pub_type

杂志文章

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Kinetic analysis of evoked IPSCs discloses mechanism of antagonism of synaptic GABAA receptors by picrotoxin.