QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text Full Text (PDF) Data Supplement All Versions of this Article: mol.105.017236v1 mol.105.017236v2 69/2/640    most recent Submit a response Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Khom, S. Articles by Hering, S. Search for Related Content PubMed PubMed Citation Articles by Khom, S. Articles by Hering, S.

Pharmacological Properties of GABA_A Receptors Containing 1 Subunits

Department of Pharmacology and Toxicology, University of Vienna (S.K., I.B., E.N.T., A.H., S.H.), and Center of Brain Research, Medical University of Vienna, Division of Biochemistry and Molecular Biology (W.S.), Vienna, Austria

GABA_A receptors composed of ₁, ₂, ₁ subunits are expressed in only a few areas of the brain and thus represent interesting drug targets. The pharmacological properties of this receptor subtype, however, are largely unknown. In the present study, we expressed ₁₂₁-GABA_A receptors in Xenopus laevis oocytes and analyzed their modulation by 21 ligands from 12 structural classes making use of the two-microelectrode voltage-clamp method and a fast perfusion system. Modulation of GABA-induced chloride currents (I_GABA) was studied at GABA concentrations eliciting 5 to 10% of the maximal response. Triazolam, clotiazepam, midazolam, 2-(4-methoxyphenyl)-2,3,5,6,7,8,9,10-octahydro-cyclohepta-(b)pyrazolo[4,3-d]pyridin-3-one (CGS 20625), 2-(4-chlorophenyl)-pyrazolo[4,3-c]quinolin-3-one (CGS 9896), diazepam, zolpidem, and bretazenil at 1 µM concentrations were able to significantly (>20%) enhance I_GABA in ₁₂₁ receptors. Methyl-6,7-dimethoxy-4-ethyl--carboline-3-carboxylate, 3-methyl-6-[3-trifluoromethyl-phenyl]-1,2,4-triazolo[4,3-b]pyridazine (Cl 218,872), clobazam, flumazenil, 5-(6-ethyl-7-methoxy-5-methylimidazo[1,2-a]pyrimidin-2-yl)-3-methyl-[1,2,4]-oxadiazole (Ru 33203), 2-phenyl-4-(3-ethyl-piperidinyl)-quinoline (PK 9084), flurazepam, ethyl-7-methoxy-11,12,13,13a-tetrahydro-9-oxo-9H-imidazo[1,5-a]pyrrolo[2,1-c] [1,4]benzodiazepine-1-carboxylate (L-655,708), 2-(6-ethyl-7-methoxy-5-methylimidazo[1,2-a]pyrimidin-2-yl)-4-methyl-thiazole (Ru 33356), and 6-ethyl-7-methoxy-5-methylimidazo[1,2-a]pyrimidin-2-yl)phenylmethanone (Ru 32698) (1 µM each) had no significant effect, and flunitrazepam and 2-phenyl-4-(4-ethyl-piperidinyl)-quinoline (PK 8165) inhibited I_GABA. The most potent compounds triazolam, clotiazepam, midazolam, and CGS 20625 were investigated in more detail on ₁₂₁ and _122S receptors. The potency and efficiency of these compounds for modulating I_GABA was smaller for ₁₂₁ than for _122S receptors, and their effects on ₁₂₁ could not be blocked by flumazenil. CGS 20625 displayed the highest efficiency by enhancing at 100 µM I_GABA (₁₂₂) by 775 ± 17% versus 526 ± 14% I_GABA (₁₂₁) and 157 ± 17% I_GABA (₁₂) (p < 0.05). These data provide new insight into the pharmacological properties of GABA_A receptors containing ₁ subunits and may aid in the design of specific ligands for this receptor subtype.

Address correspondence to: Dr. Steffen Hering, Department of Pharmacology and Toxicology, University of Vienna, Althanstrasse 14, A-1090 Vienna, Austria. E-mail: steffen.hering{at}univie.ac.at

This article has been cited by other articles:

				R. W. Olsen and W. Sieghart International Union of Pharmacology. LXX. Subtypes of {gamma}-Aminobutyric AcidA Receptors: Classification on the Basis of Subunit Composition, Pharmacology, and Function. Update Pharmacol. Rev., September 1, 2008; 60(3): 243 - 260. [Abstract] [Full Text] [PDF]