Subunit Composition, Distribution and Function of GABA-A Receptor Subtypes

Sieghart, Werner; Sperk, Günther

doi:10.2174/1568026023393507

Cited by 824 publications

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“…The GABA A receptor is putatively a pentamer comprising subunits of the GABA A receptor family, with most native receptors containing two a, two b, and a single g subunit (Sieghart and Sperk, 2002). As a result the benzodiazepinebinding site occurs at the junction of the a and g subunits and because most native GABA A receptors contain the g2 Comparison of the effect of FG 7142 on feeding microstructure with those of other anorectic drugs (naltrexone, fenfluramine and leptin) as well as with psychosocial stressors (30-min restraint or resident-intruder) that have been tested in the validated drinking-inclusive meal definition (Zorrilla et al, 2005a).…”

Section: Discussionmentioning

confidence: 99%

FG 7142 Specifically Reduces Meal Size and the Rate and Regularity of Sustained Feeding in Female Rats: Evidence that Benzodiazepine Inverse Agonists Reduce Food Palatability

Cottone

Sabino

Steardo

et al. 2006

Neuropsychopharmacol

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Benzodiazepine receptor inverse agonists reduce food intake in males, but their actions in females, in whom stress-related eating disorders are more common, as well as their behavioral mode of action remain unclear. The consummatory effects of benzodiazepine receptor ligands have alternately been hypothesized to reflect changes in the hedonic evaluation of food or secondary effects of anxietyrelated or cognitive properties. To test the anorectic mode of action of benzodiazepine inverse agonists, the effects of FG 7142 on feeding microstructure were studied in nondeprived female Wistar rats (n ¼ 32). Microstructure analysis used a novel meal definition that recognizes prandial drinking. On pharmacologically synchronized diestrus I, rats were pretreated (À30 min dark onset) with the benzodiazepine partial inverse agonist FG 7142 (i.p. 0, 3.75, 7.5, 15 mg/kg) in a between-subjects design. FG 7142 delayed the onset of (16-541%), decreased the amount eaten (36-52%) and drunk (63-87%), and reduced the time spent drinking (59-87%) within the first nocturnal meal. Dose-dependent incremental anorexia continued 6 h into the dark cycle, whereas FG 7142 did not suppress the quantity, duration or rate of drinking past the first meal. Treated rats ate smaller meals (17-42%) of normal duration. This reflected that FG 7142 slowed feeding within meals (9-38%) by decreasing the regularity and maintenance of feeding from pellet-to-pellet. FG 7142 did not influence postprandial satiety; meal frequency and inter-meal intervals were unaffected. FG 7142 anorexia was blocked by the benzodiazepine receptor antagonist flumazenil in a 2:1 molar ratio (n ¼ 17 rats). The very early, nonspecific ( + 10 min), but not subsequent (2.5, 4.5 h) feeding-specific phase, of FG 7142 anorexia was mirrored by anxiogenic-like behavior in FG 7142-treated (7.5 mg/ kg) female rats (n ¼ 48) in the elevated plus-maze. Thus, benzodiazepine receptor inverse agonists preferentially lessen the maintenance of feeding in female rats, effects opposite to those of palatable food.

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Section: Discussionmentioning

confidence: 99%

FG 7142 Specifically Reduces Meal Size and the Rate and Regularity of Sustained Feeding in Female Rats: Evidence that Benzodiazepine Inverse Agonists Reduce Food Palatability

Cottone

Sabino

Steardo

et al. 2006

Neuropsychopharmacol

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“…The most common combination of a GABA A receptor is αβγ, in which α and β subunits appear to be essential and the γ subunit can be replaced by other subunits (Sieghart et al, 1999). In addition to those common subunits, "rare" subunits such as θ, ε, δ and π can assemble with αβγ (Sieghart and Sperk, 2002;Sieghart et al, 1999). For example, the π subunit was found to assemble with α1β3γ2 or α5β3γ3 in the co-transfected cell lines (Hedblom and Kirkness, 1997;Neelands and Macdonald, 1999).…”

Section: Nih Public Accessmentioning

confidence: 99%

Ionotropic GABA receptor expression in the lung during development

Jin

Guo

Sun

et al. 2008

Gene Expression Patterns

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Cl − transport is essential for lung development. Because gamma-aminobutyric acid (GABA) receptors allow the flow of negatively-charged Cl − ions across the cell membrane, we hypothesized that the expression of ionotropic GABA receptors are regulated in the lungs during development. We identified 17 GABA receptor subunits in the lungs by real-time PCR. These subunits were categorized into 4 groups: Group 1 had high mRNA expression during fetal stages and low in adults; Group 2 had steady expression to adult stages with a slight up-regulation at birth; Group 3 showed an increasing expression from fetal to adult lungs; and Group 4 displayed irregular mRNA fluctuations. The protein levels of selected subunits were also determined by Western blots and some subunits had protein levels that corresponded to mRNA levels. Further studied subunits were primarily localized in epithelial cells in the developing lung with differential mRNA expression between isolated cells and whole lung tissues. Our results add to the knowledge of GABA receptor expression in the lung during development. Keywordslungs; ionotropic GABA receptor; fetal lung development; chloride homeostasis; lung fluid transport; real time PCR; gene expression; alveolar epithelial cells RESULTS AND DISCUSSION SignificanceCl − channels play an important role in the lung throughout an animal's life. During the fetal stages, the lung is a fluid-secreting organ. The main driving force for fluid secretion is the active secretion of Cl − into the developing lungs. Therefore, Cl − channels are indispensable for fetal lung development and morphogenesis (Folkesson et al., 1998;Olver et al., 2004;Bland and Nielson, 1992). On the other hand, the adult lung is air-filled and maintains a "dry" state. The apical surface is covered by a thin layer of alveolar surface fluid. This layer of fluid is required for the proper air exchange and airway defenses. Cl − channels are also essential for maintaining the composition and volume of the alveolar surface fluid (Brochiero et al., 2004 Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. Several Cl − channels have previously been studied in the lung. The cystic fibrosis transmembrane conductance regulator (CFTR) (Harris et al., 1991), the voltage-gated Cl − channels, ClC2 (Thiemann et al., 1992), ClC3 (Lamb et al., 2001), and ClC5 (Edmonds et al., 2002, and Na + -K + -Cl − cotransporter (NKCC) (Rochelle et al., 2000) have been detected in fetal lungs, distal airway epithelial cells and alveolar epithelial cells. Some of the channels have been shown to be involved in fluid homeostasis i...

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“…The basic characterization of the diverse pharmacological effects of BZs: anxiolytic, sedative, hypnotic, muscle relaxant, anticonvulsive, and amnesic, has been considered to represent one of the major successes of behavioral pharmacology (Sanger et al, 2003). In recent years, much effort has been expended to improve the understanding of the molecular and neuronal substrates of these effects, with the final goal to clinically separate wanted from unwanted effects (Sieghart and Sperk, 2002). Among the latter effects, psychomotor and cognitive impairments are common, and more serious neuropsychiatric reactions such as amnesic and aggressive episodes may occur (Lader, 1999).…”

Section: Introductionmentioning

confidence: 99%

Are GABAA Receptors Containing α5 Subunits Contributing to the Sedative Properties of Benzodiazepine Site Agonists?

Savić

Huang

Furtmüller

et al. 2007

Neuropsychopharmacol

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Classical benzodiazepines (BZs) exert anxiolytic, sedative, hypnotic, muscle relaxant, anticonvulsive, and amnesic effects through potentiation of neurotransmission at GABA A receptors containing a 1 , a 2 , a 3 or a 5 subunits. Genetic studies suggest that modulation at the a 1 subunit contributes to much of the adverse effects of BZs, most notably sedation, ataxia, and amnesia. Hence, BZ site ligands functionally inactive at GABA A receptors containing the a 1 subunit are considered to be promising leads for novel, anxioselective anxiolytics devoid of sedative properties. In pursuing this approach, we used two-electrode voltage clamp experiments in Xenopus oocytes expressing recombinant GABA A receptor subtypes to investigate functional selectivity of three newly synthesized BZ site ligands and also compared their in vivo behavioral profiles. The compounds were functionally selective for a 2 -, a 3 -, and a 5 -containing subtypes of GABA A receptors (SH-053-S-CH3 and SH-053-S-CH3-2 0 F) or essentially selective for a 5 subtypes (SH-053-R-CH3). Possible influences on behavioral measures were tested in the elevated plus maze, spontaneous locomotor activity, and rotarod test, which are considered primarily predictive of the anxiolytic, sedative, and ataxic influence of BZs, respectively. The results confirmed the substantially diminished ataxic potential of BZ site agonists devoid of a 1 subunit-mediated effects, with preserved anti-anxiety effects at 30 mg/kg of SH-053-S-CH3 and SH-053-S-CH3-2 0 F. However, all three ligands, dosed at 30 mg/kg, decreased spontaneous locomotor activity, suggesting that sedation may be partly dependent on activity mediated by a 5 -containing GABA A receptors. Hence, it could be of importance to avoid substantial agonist activity at a 5 receptors by candidate anxioselective anxiolytics, if clinical sedation is to be avoided.

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Subunit Composition, Distribution and Function of GABA-A Receptor Subtypes

Cited by 824 publications

References 0 publications

FG 7142 Specifically Reduces Meal Size and the Rate and Regularity of Sustained Feeding in Female Rats: Evidence that Benzodiazepine Inverse Agonists Reduce Food Palatability

FG 7142 Specifically Reduces Meal Size and the Rate and Regularity of Sustained Feeding in Female Rats: Evidence that Benzodiazepine Inverse Agonists Reduce Food Palatability

Ionotropic GABA receptor expression in the lung during development

Are GABAA Receptors Containing α5 Subunits Contributing to the Sedative Properties of Benzodiazepine Site Agonists?

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