Click here to close
Hello! We notice that you are using Internet Explorer, which is not supported by Xenbase and may cause the site to display incorrectly.
We suggest using a current version of Chrome,
FireFox, or Safari.
Br J Pharmacol
1999 May 01;1271:57-64. doi: 10.1038/sj.bjp.0702504.
Show Gene links
Show Anatomy links
Antagonistic action of pitrazepin on human and rat GABA(A) receptors.
Demuro A
,
Martinez-Torres A
,
Francesconi W
,
Miledi R
.
???displayArticle.abstract???
Pitrazepin, 3-(piperazinyl-1)-9H-dibenz(c,f) triazolo(4,5-a)azepin is a piperazine antagonist of GABA in a variety of electrophysiological and in vitro binding studies involving GABA and glycine receptors. In the present study we have investigated the effects of pitrazepin, and the GABA(A) antagonist bicuculline, on membrane currents elicited by GABA in Xenopus oocytes injected with rat cerebral cortex mRNA or cDNAs encoding alpha1beta2 or alpha1beta2gamma2s human GABA(A) receptor subunits. The three types of GABA(A) receptors expressed were reversibly antagonized by bicuculline and pitrazepin in a concentration-dependent manner. GABA dose-current response curves for the three types of receptors were shifted to the right, in a parallel manner, by increasing concentrations of pitrazepin. Schild analyses gave pA2 values of 6.42+/-0.62, n = 4, 6.41+/-1.2, n = 5 and 6.21+/-1.24, n = 6, in oocytes expressing rat cerebral cortex, alpha1beta2 or alpha1beta2gamma2s human GABA(A) receptors respectively (values are given as means +/- s.e. mean), and the Hill coefficients were all close to unity. All this is consistent with the notion that pitrazepin acts as a competitive antagonist of these GABA(A) receptors; and that their antagonism by pitrazepin is not strongly dependent on the subunit composition of the receptors here studied. Since pitrazepin has been reported to act also at the benzodiazepine binding site, we studied the effect of the benzodiazepine antagonist Ro 15-1788 (flumazenil) on the inhibition of alpha1beta2gamma2s receptors by pitrazepin. Co-application of Ro 15-1788 did not alter the inhibiting effect of pitrazepin. Moreover, pitrazepin did not antagonize the potentiation of GABA-currents by flunitrazepam. All this suggests that pitrazepin does not affect the GABA receptor-chloride channel by interacting with the benzodiazepine receptor site.
Angelotti,
Assembly of GABAA receptor subunits: analysis of transient single-cell expression utilizing a fluorescent substrate/marker gene technique.
1993, Pubmed
Angelotti,
Assembly of GABAA receptor subunits: analysis of transient single-cell expression utilizing a fluorescent substrate/marker gene technique.
1993,
Pubmed
Bormann,
gamma-Aminobutyric acid receptor channels in adrenal chromaffin cells: a patch-clamp study.
1985,
Pubmed
Bormann,
Chloride channels in the mammalian central nervous system.
1989,
Pubmed
Braestrup,
Interaction of pitrazepin with the GABA/benzodiazepine receptor complex and with glycine receptors.
1985,
Pubmed
Burt,
GABAA receptor subtypes: from pharmacology to molecular biology.
1991,
Pubmed
Choi,
GABA conductance of chick spinal cord and dorsal root ganglion neurons in cell culture.
1981,
Pubmed
Chomczynski,
Single-step method of RNA isolation by acid guanidinium thiocyanate-phenol-chloroform extraction.
1987,
Pubmed
Dominguez-Perrot,
Recombinant GABAA receptor desensitization: the role of the gamma 2 subunit and its physiological significance.
1996,
Pubmed
Fritschy,
Five subtypes of type A gamma-aminobutyric acid receptors identified in neurons by double and triple immunofluorescence staining with subunit-specific antibodies.
1992,
Pubmed
Gähwiler,
Pitrazepin, a novel GABAA antagonist.
1984,
Pubmed
Gao,
Selective allocation of GABAA receptors containing the alpha 1 subunit to neurochemically distinct subpopulations of rat hippocampal interneurons.
1994,
Pubmed
Gundersen,
Messenger RNA from human brain induces drug- and voltage-operated channels in Xenopus oocytes.
,
Pubmed
,
Xenbase
Günther,
Benzodiazepine-insensitive mice generated by targeted disruption of the gamma 2 subunit gene of gamma-aminobutyric acid type A receptors.
1995,
Pubmed
Hattori,
Internal perfusion studies demonstrating GABA-induced chloride responses in frog primary afferent neurons.
1984,
Pubmed
Kemp,
Quantitative evaluation of the potencies of GABA-receptor agonists and antagonists using the rat hippocampal slice preparation.
1986,
Pubmed
Krishek,
A functional comparison of the antagonists bicuculline and picrotoxin at recombinant GABAA receptors.
1996,
Pubmed
,
Xenbase
Kusano,
Cholinergic and catecholaminergic receptors in the Xenopus oocyte membrane.
1982,
Pubmed
,
Xenbase
Levitan,
Structural and functional basis for GABAA receptor heterogeneity.
1988,
Pubmed
,
Xenbase
Lüddens,
Cerebellar GABAA receptor selective for a behavioural alcohol antagonist.
1990,
Pubmed
McKernan,
Which GABAA-receptor subtypes really occur in the brain?
1996,
Pubmed
Miledi,
A calcium-dependent transient outward current in Xenopus laevis oocytes.
1982,
Pubmed
,
Xenbase
Miledi,
Synthesis of chick brain GABA receptors by frog oocytes.
1982,
Pubmed
,
Xenbase
Nguyen,
A Windows software package to record from voltage-clamped Xenopus oocytes.
1995,
Pubmed
,
Xenbase
Parker,
Actions of pentobarbital on rat brain receptors expressed in Xenopus oocytes.
1986,
Pubmed
,
Xenbase
Polenzani,
Expression of mammalian gamma-aminobutyric acid receptors with distinct pharmacology in Xenopus oocytes.
1991,
Pubmed
,
Xenbase
Pritchett,
Importance of a novel GABAA receptor subunit for benzodiazepine pharmacology.
1989,
Pubmed
Pritchett,
Type I and type II GABAA-benzodiazepine receptors produced in transfected cells.
1989,
Pubmed
Puia,
Influence of recombinant gamma-aminobutyric acid-A receptor subunit composition on the action of allosteric modulators of gamma-aminobutyric acid-gated Cl- currents.
1991,
Pubmed
Sigel,
The effect of subunit composition of rat brain GABAA receptors on channel function.
1990,
Pubmed
,
Xenbase
Simmonds,
Classification of some GABA antagonists with regard to site of action and potency in slices of rat cuneate nucleus.
1982,
Pubmed
Smart,
mRNA-directed synthesis and insertion of functional amino acid receptors in Xenopus laevis oocytes.
1987,
Pubmed
,
Xenbase
Smart,
GABAA receptors are differentially sensitive to zinc: dependence on subunit composition.
1991,
Pubmed
Squires,
Mono N-aryl ethylenediamine and piperazine derivatives are GABAA receptor blockers: implications for psychiatry.
1993,
Pubmed
Squires,
Antidepressants and metabolites that block GABAA receptors coupled to 35S-t-butylbicyclophosphorothionate binding sites in rat brain.
1988,
Pubmed
Squires,
GABAA receptor blockers reverse the inhibitory effect of GABA on brain-specific [35S]TBPS binding.
1987,
Pubmed
Squires,
A review of evidence for GABergic predominance/glutamatergic deficit as a common etiological factor in both schizophrenia and affective psychoses: more support for a continuum hypothesis of "functional" psychosis.
1991,
Pubmed
Ueno,
Bicuculline and gabazine are allosteric inhibitors of channel opening of the GABAA receptor.
1997,
Pubmed
Whiting,
Structure and pharmacology of vertebrate GABAA receptor subtypes.
1995,
Pubmed
Woodward,
Characterization of bicuculline/baclofen-insensitive (rho-like) gamma-aminobutyric acid receptors expressed in Xenopus oocytes. II. Pharmacology of gamma-aminobutyric acidA and gamma-aminobutyric acidB receptor agonists and antagonists.
1993,
Pubmed
,
Xenbase