Home About us Contact
|
Home About us Contact | ||
|
|
||
GABAA Receptor Subtypes (gabaa + receptor_subtype)
Selected AbstractsThe insecticide fipronil and its metabolite fipronil sulphone inhibit the rat ,1,2,2L GABAA receptorBRITISH JOURNAL OF PHARMACOLOGY, Issue 5 2008Background and purpose: Fipronil is the active ingredient in a number of widely used insecticides. Human exposure to fipronil leads to symptoms (headache, nausea and seizures) typically associated with the antagonism of GABAA receptors in the brain. In this study, we have examined the modulation of the common brain GABAA receptor subtype by fipronil and its major metabolite, fipronil sulphone. Experimental approach: Whole-cell and single-channel recordings were made from HEK 293 cells transiently expressing rat ,1,2,2L GABAA receptors. Key results: The major effect of fipronil was to increase the rate of current decay in macroscopic recordings. In single-channel recordings, the presence of fipronil resulted in shorter cluster durations without affecting the intracluster open and closed time distributions or the single-channel conductance. The ,1V256S mutation, previously shown alleviate channel inhibition by inhibitory steroids and several insecticides, had a relatively small effect on channel block by fipronil. The mode of action of fipronil sulphone was similar to that of its parent compound but the metabolite was less potent at inhibiting the ,1,2,2L receptor. Conclusions and implications: We conclude that exposure to fipronil induces accumulation of receptors in a novel, long-lived blocked state. This process proceeds in parallel with and independently of, channel desensitization. The lower potency of fipronil sulphone indicates that the conversion serves as a detoxifying process in mammalian brain. British Journal of Pharmacology (2008) 155, 783,794; doi:10.1038/bjp.2008.309; published online 28 July 2008 [source] Rescue of ,2 subunit-deficient mice by transgenic overexpression of the GABAA receptor ,2S or ,2L subunit isoformsEUROPEAN JOURNAL OF NEUROSCIENCE, Issue 7 2000Kristin Baer Abstract The ,2 subunit is an important functional determinant of GABAA receptors and is essential for formation of high-affinity benzodiazepine binding sites and for synaptic clustering of major GABAA receptor subtypes along with gephyrin. There are two splice variants of the ,2 subunit, ,2 short (,2S) and ,2 long (,2L), the latter carrying in the cytoplasmic domain an additional eight amino acids with a putative phosphorylation site. Here, we show that transgenic mice expressing either the ,2S or ,2L subunit on a ,2 subunit-deficient background are phenotypically indistinguishable from wild-type. They express nearly normal levels of ,2 subunit protein and [3H]flumazenil binding sites. Likewise, the distribution, number and size of GABAA receptor clusters colocalized with gephyrin are similar to wild-type in both juvenile and adult mice. Our results indicate that the two ,2 subunit splice variants can substitute for each other and fulfil the basic functions of GABAA receptors, allowing in vivo studies that address isoform-specific roles in phosphorylation-dependent regulatory mechanisms. [source] Molecular regulation of cognitive functions and developmental plasticity: impact of GABAA receptorsJOURNAL OF NEUROCHEMISTRY, Issue 1 2007Hanns Möhler Abstract By controlling spike timing and sculpting neuronal rhythms, inhibitory interneurons play a key role in regulating neuronal circuits and behavior. The pronounced diversity of GABAergic (,-aminobutyric acid) interneurons is paralleled by an extensive diversity of GABAA receptor subtypes. The region- and domain-specific location of these receptor subtypes offers the opportunity to gain functional insights into the role of defined neuronal circuits. These developments are reviewed with regard to the regulation of sleep, anxiety, memory, sensorimotor processing and post-natal developmental plasticity. [source] Effects of Serotonin, GABA and Neuropeptide Y on Seabream Gonadotropin Releasing Hormone Release In Vitro from Preoptic-Anterior Hypothalamus and Pituitary of Red Seabream, Pagrus majorJOURNAL OF NEUROENDOCRINOLOGY, Issue 5 2001B. Senthilkumaran Abstract The effects of serotonin (5-HT), GABA and neuropeptide Y (NPY) on in vitro release of seabream (sb) gonadotropin releasing hormone (GnRH) from slices of the preoptic-anterior hypothalamus (P-AH) and pituitary of red seabream were studied. 5-HT, GABA and NPY all stimulated the release of sbGnRH from the P-AH but not from the pituitary of immature red seabream. They also stimulated sbGnRH release from the P-AH with a similar potency during the course of gonadal development. Specific agonists and/or antagonists of 5-HT, GABA and NPY showed that 5-HT and GABA utilize 5-HT2 and GABAA receptor subtypes, respectively, to mediate their action, and that NPY employs at least NPYY1 and NPYY2 receptor subtypes to stimulate sbGnRH release. Combinations of different antagonists for 5-HT, GABA and noradrenaline/adrenaline did not block the stimulatory influence of NPY on release of sbGnRH, indicating that the action of NPY on the sbGnRH neuronal system is probably direct. [source] Zolpidem Generalization and Antagonism in Male and Female Cynomolgus Monkeys Trained to Discriminate 1.0 or 2.0 g,/,kg EthanolALCOHOLISM, Issue 7 2008Christa M. Helms Background:, The subtypes of , -aminobutyric acid (GABA)A receptors mediating the discriminative stimulus effects of ethanol in nonhuman primates are not completely identified. The GABAA receptor positive modulator zolpidem has high, intermediate, and low activity at receptors containing ,1, ,2/3, and ,5 subunits, respectively, and partially generalizes from ethanol in several species. The partial inverse agonist Ro15-4513 has the greatest affinity for ,4/6 -containing receptors, higher affinity for ,5 - and lower, but equal, affinity for ,1 - and ,2/3 -, containing GABAA receptors, and antagonizes the discriminative stimulus effects of ethanol. Methods:, This study assessed Ro15-4513 antagonism of the generalization of zolpidem from ethanol in male (n = 9) and female (n = 8) cynomolgus monkeys (Macaca fascicularis) trained to discriminate 1.0 g/kg (n = 10) or 2.0 g/kg (n = 7) ethanol (i.g.) from water with a 30-minute pretreatment interval. Results:, Zolpidem (0.017 to 5.6 mg/kg, i.m.) completely generalized from ethanol (,80% of total session responses on the ethanol-appropriate lever) for 6/7 monkeys trained to discriminate 2.0 g/kg and 4/10 monkeys trained to discriminate 1.0 g/kg ethanol. Zolpidem partially generalized from 1.0 or 2.0 g/kg ethanol in 6/7 remaining monkeys. Ro15-4513 (0.003 to 0.30 mg/kg, i.m., 5-minute pretreatment) shifted the zolpidem dose,response curve to the right in all monkeys showing generalization. Analysis of apparent pKB from antagonism tests suggested that the discriminative stimulus effects of ethanol common with zolpidem are mediated by low-affinity Ro15-4513 binding sites. Main effects of sex and training dose indicated greater potency of Ro15-4513 in males and in monkeys trained to discriminate 1.0 g/kg ethanol. Conclusions:, Ethanol and zolpidem share similar discriminative stimulus effects most likely through GABAA receptors that contain ,1 subunits, however, antagonism by Ro15-4513 of zolpidem generalization from the lower training dose of ethanol (1.0 g/kg) may involve additional zolpidem-sensitive GABAA receptor subtypes (e.g., ,2/3 and ,5). [source] | |||||||||||||