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Molecular tools for GABA_A receptors: High affinity ligands for ?1-containing subtypes.

ABSTRACT: ?-Aminobutyric acid type A (GABA_A) receptors are pentameric GABA-gated chloride channels that are, in mammalians, drawn from a repertoire of 19 different genes, namely ?1-6, ?1-3, ?1-3, ?, ?, ?, ? and ?1-3. The existence of this wide variety of subunits as well as their diverse assembly into different subunit compositions result in miscellaneous receptor subtypes. In combination with the large number of known and putative allosteric binding sites, this leads to a highly complex pharmacology. Recently, a novel binding site at extracellular ?+/?- interfaces was described as the site of modulatory action of several pyrazoloquinolinones. In this study we report a highly potent ligand from this class of compounds with pronounced ?1-selectivity that mainly lacks ?-subunit selectivity. It constitutes the most potent ?1-selective positive allosteric modulatory ligand with known binding site. In addition, a proof of concept pyrazoloquinolinone ligand lacking the additional high affinity interaction with the benzodiazepine binding site is presented. Ultimately, such ligands can be used as invaluable molecular tools for the detection of ?1-containing receptor subtypes and the investigation of their abundance and distribution.

SUBMITTER: Simeone X

PROVIDER: S-EPMC5516028 | biostudies-literature | 2017 Jul

REPOSITORIES: biostudies-literature

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Molecular tools for GABA<sub>A</sub> receptors: High affinity ligands for β1-containing subtypes.

Simeone Xenia X Siebert David C B DCB Bampali Konstantina K Varagic Zdravko Z Treven Marco M Rehman Sabah S Pyszkowski Jakob J Holzinger Raphael R Steudle Friederike F Scholze Petra P Mihovilovic Marko D MD Schnürch Michael M Ernst Margot M

Scientific reports 20170718 1

γ-Aminobutyric acid type A (GABA<sub>A</sub>) receptors are pentameric GABA-gated chloride channels that are, in mammalians, drawn from a repertoire of 19 different genes, namely α1-6, β1-3, γ1-3, δ, ε, θ, π and ρ1-3. The existence of this wide variety of subunits as well as their diverse assembly into different subunit compositions result in miscellaneous receptor subtypes. In combination with the large number of known and putative allosteric binding sites, this leads to a highly complex pharma ...[more]

PMID: 28720884

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Project description:GABAA receptors containing the α5 subunit mediate tonic inhibition and are widely expressed in the limbic system. In animals, activation of α5-containing receptors impairs hippocampus-dependent memory. Temporal lobe epilepsy is associated with memory impairments related to neuron loss and other changes. The less selective PET ligand [11C]flumazenil has revealed reductions in GABAA receptors. The hypothesis that α5 subunit receptor alterations are present in temporal lobe epilepsy and could contribute to impaired memory is untested. We compared α5 subunit availability between individuals with temporal lobe epilepsy and normal structural MRI ('MRI-negative') and healthy controls, and interrogated the relationship between α5 subunit availability and episodic memory performance, in a cross-sectional study. Twenty-three healthy male controls (median ± interquartile age 49 ± 13 years) and 11 individuals with MRI-negative temporal lobe epilepsy (seven males; 40 ± 8) had a 90-min PET scan after bolus injection of [11C]Ro15-4513, with arterial blood sampling and metabolite correction. All those with epilepsy and six controls completed the Adult Memory and Information Processing Battery on the scanning day. 'Bandpass' exponential spectral analyses were used to calculate volumes of distribution separately for the fast component [V F; dominated by signal from α1 (α2, α3)-containing receptors] and the slow component (V S; dominated by signal from α5-containing receptors). We made voxel-by-voxel comparisons between: the epilepsy and control groups; each individual case versus the controls. We obtained parametric maps of V F and V S measures from a single bolus injection of [11C]Ro15-4513. The epilepsy group had higher V S in anterior medial and lateral aspects of the temporal lobes, the anterior cingulate gyri, the presumed area tempestas (piriform cortex) and the insulae, in addition to increases of ∼24% and ∼26% in the ipsilateral and contralateral hippocampal areas (P < 0.004). This was associated with reduced V F:V S ratios within the same areas (P < 0.009). Comparisons of V S for each individual with epilepsy versus controls did not consistently lateralize the epileptogenic lobe. Memory scores were significantly lower in the epilepsy group than in controls (mean ± standard deviation -0.4 ± 1.0 versus 0.7 ± 0.3; P = 0.02). In individuals with epilepsy, hippocampal V S did not correlate with memory performance on the Adult Memory and Information Processing Battery. They had reduced V F in the hippocampal area, which was significant ipsilaterally (P = 0.03), as expected from [11C]flumazenil studies. We found increased tonic inhibitory neurotransmission in our cohort of MRI-negative temporal lobe epilepsy who also had co-morbid memory impairments. Our findings are consistent with a subunit shift from α1/2/3 to α5 in MRI-negative temporal lobe epilepsy.

Project description:Background and purposeThe pathophysiological role of ?6 -subunit-containing GABAA receptors, which are mainly expressed in cerebellar granule cells, remains unclear. Recently, we demonstrated that hispidulin, a flavonoid isolated from a local herb that remitted a patient's intractable motor tics, attenuated methamphetamine-induced hyperlocomotion in mice as a positive allosteric modulator (PAM) of cerebellar ?6 GABAA receptors. Here, using hispidulin and a selective ?6 GABAA receptor PAM, the pyrazoloquinolinone Compound 6, we revealed an unprecedented role of cerebellar ?6 GABAA receptors in disrupted prepulse inhibition of the startle response (PPI), which reflects sensorimotor gating deficits manifested in several neuropsychiatric disorders.Experimental approachPPI disruptions were induced by methamphetamine and NMDA receptor antagonists in mice. Effects of the tested compounds were measured in Xenopus oocytes expressing recombinant ?6 ?3 ?2S GABAA receptors.Key resultsHispidulin given i.p. or by bilateral intracerebellar (i.cb.) injection rescued PPI disruptions induced by methamphetamine, ketamine, MK-801 and phencyclidine. Intracerebellar effects of hispidulin were mimicked by Ro15-4513 and loreclezole (two ?6 GABAA receptor PAMs), but not by diazepam (an ?6 GABAA receptor-inactive benzodiazepine) and were antagonized by furosemide (i.cb.), an ?6 GABAA receptor antagonist. Importantly, Compound 6 (i.p.) also rescued methamphetamine-induced PPI disruption, an effect prevented by furosemide (i.cb.). Both hispidulin and Compound 6 potentiated ?6 ?3 ?2S GABAA receptor-mediated GABA currents.Conclusions and implicationsPositive allosteric modulation of cerebellar ?6 GABAA receptors rescued disrupted PPI by attenuating granule cell activity. ?6 GABAA receptor-selective PAMs are potential medicines for treating sensorimotor gating deficits in neuropsychiatric disorders. A mechanistic hypothesis is based on evidence for cerebellar contributions to cognitive functioning including sensorimotor gating.

Dataset Information

Molecular tools for GABAA receptors: High affinity ligands for ?1-containing subtypes.

Publications

Molecular tools for GABA<sub>A</sub> receptors: High affinity ligands for β1-containing subtypes.

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Molecular tools for GABA_A receptors: High affinity ligands for ?1-containing subtypes.