Pharmacological characterization of a novel positive modulator at α4β3δ-containing extrasynaptic GABAA receptors

Hoestgaard-Jensen, Kirsten; Dalby, Nils Ole; Wolinsky, Toni D.; Murphey, C. R.; Jones, Kenneth A.; Rottländer, Mario; Frederiksen, Kristen; Watson, William P.; Jensen, Kimmo; Ebert, Bjarke

doi:10.1016/j.neuropharm.2009.12.023

Cited by 29 publications

(33 citation statements)

References 33 publications

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“…Although our understanding of the physiological role of these receptors has advanced, given the limited availability of pharmacological tools that target d-GABAA receptors, the following discussion compares, where applicable, the profile of DS2 to the only well-described d-GABAA receptor selective tool gaboxadol. In addition, two other putative d-GABAA receptor-preferring compounds have recently been described, namely the trimethylbenzylamino compound AA29504 (Hoestgaard-Jensen et al, 2010) and a dihydropyrimidinone compound JM-II-43A (Lewis et al, 2010). Therefore, where relevant data are available on these molecules, comparisons are made with our data on DS2.…”

Section: Tablementioning

confidence: 97%

“…Although data on AA29504 (Hoestgaard-Jensen et al, 2010) and JM-II-43A (Lewis et al, 2010) are either limited, or the methodologies and techniques differ from those used here, some comparison with the selectivity profile of DS2 is possible. AA29504 was tested on a4b3d and a1b3g2s receptors; and, in common with DS2, this compound preferentially modulates a4b3d over a1b3g2S receptors (Hoestgaard-Jensen et al, 2010).…”

Section: Gaba a Receptor Subtype Selectivitymentioning

confidence: 99%

“…AA29504 was tested on a4b3d and a1b3g2s receptors; and, in common with DS2, this compound preferentially modulates a4b3d over a1b3g2S receptors (Hoestgaard-Jensen et al, 2010). However, in more detailed studies addressing the mechanism of action of AA29504, the authors showed that it decreased the EC50 for GABA acting at both a4b3d-and a1b3g2S-receptors.…”

Section: Gaba a Receptor Subtype Selectivitymentioning

confidence: 99%

“…The imidazopyridine DS2 is a functionally selective a4b3d PAM, relative to its actions at a4b3g2 and a1b3g2 receptors, with clear effects on the tonic current of thalamic ventrobasal (VB) neurons mediated by a4b2d receptors (Wafford et al, 2009). Recently, the triamino-benzene compound AA29504, a retigabine analogue, was described as a functionally selective a4b3d PAM, albeit the lack of full concentrationresponse analysis at d-and g-containing GABAA receptors precludes definitive conclusions (Hoestgaard-Jensen et al, 2010). Nonetheless, AA29504 augments the effects of gaboxadol in cortical brain slices, enters the brain and is effective in some in vivo models.…”

Section: Introductionmentioning

confidence: 99%

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A study of subunit selectivity, mechanism and site of action of the delta selective compound 2 (DS2) at human recombinant and rodent native GABA_A receptors

Wafford

Brown

et al. 2013

British J Pharmacology

101

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BACKGROUND AND PURPOSEMost GABAA receptor subtypes comprise 2a, 2b and 1g subunit, although for some isoforms, a d replaces a g-subunit. Extrasynaptic d-GABAA receptors are important therapeutic targets, but there are few suitable pharmacological tools. We profiled DS2, the purported positive allosteric modulator (PAM) of d-GABAA receptors to better understand subtype selectivity, mechanism/site of action and activity at native d-GABAA receptors. EXPERIMENTAL APPROACHSubunit specificity of DS2 was determined using electrophysiological recordings of Xenopus laevis oocytes expressing human recombinant GABAA receptor isoforms. Effects of DS2 on GABA concentration-response curves were assessed to define mechanisms of action. Radioligand binding and electrophysiology utilising mutant receptors and pharmacology were used to define site of action. Using brain-slice electrophysiology, we assessed the influence of DS2 on thalamic inhibition in wild-type and d 0/0 mice. KEY RESULTSActions of DS2 were primarily determined by the d-subunit but were additionally influenced by the a, but not the b, subunit (a4/6bxd > a1bxd >> g2-GABAA receptors > a4b3). For d-GABAA receptors, DS2 enhanced maximum responses to GABA, with minimal influence on GABA potency. (iii) DS2 did not act via the orthosteric, or known modulatory sites on GABAA receptors. (iv) DS2 enhanced tonic currents of thalamocortical neurones from wild-type but not d 0/0 mice. CONCLUSIONS AND IMPLICATIONSDS2 is the first PAM selective for a4/6bxd receptors, providing a novel tool to investigate extrasynaptic d-GABAA receptors. The effects of DS2 are mediated by an unknown site leading to GABAA receptor isoform selectivity. AbbreviationsDS1, delta selective compound 1; DS2, delta selective compound 2; ECx, effective concentration giving the activation degree of X;

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Section: Tablementioning

confidence: 97%

Section: Gaba a Receptor Subtype Selectivitymentioning

confidence: 99%

Section: Gaba a Receptor Subtype Selectivitymentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

A study of subunit selectivity, mechanism and site of action of the delta selective compound 2 (DS2) at human recombinant and rodent native GABA_A receptors

Wafford

Brown

et al. 2013

British J Pharmacology

101

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“…For example, there are conflicting reports on the GABA concentration-response relationship. Several studies had observed GABA activation curves for a4bd receptors in Xenopus oocytes with half-maximal concentrations at 1-3 mM (Storustovu and Ebert, 2006;You and Dunn, 2007;Hoestgaard-Jensen et al, 2010). In contrast, Karim et al (2012) found that the GABA activation curve for a4b3d receptors expressed in Xenopus oocytes contained two components: one with the concentration of GABA producing a halfmaximal response (EC 50 ) at ∼10 nM, the other with the EC 50 at ∼1 mM.…”

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confidence: 99%

γ-Aminobutyric Acid Type A α4, β2, and δ Subunits Assemble to Produce More Than One Functionally Distinct Receptor Type

et al. 2014

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Native g-aminobutyric acid (GABA) A receptors consisting of a4, b1-3, and d subunits mediate responses to the low, tonic concentration of GABA present in the extracellular milieu. Previous studies on heterologously expressed a4bd receptors have shown a large degree of variability in functional properties, including sensitivity to the transmitter. We studied properties of a4b2d receptors employing free subunits and concatemeric constructs, expressed in Xenopus oocytes, HEK 293 cells, and cultured hippocampal neurons. The expression system had a strong effect on the properties of receptors containing free subunits. The midpoint of GABA activation curve was 10 nM for receptors in oocytes versus 2300 nM in HEK cells. Receptors activated by the steroid alfaxalone had an estimated maximal open probability of 0.6 in oocytes and 0.01 in HEK cells. Irrespective of the expression system, receptors resulting from combining the tandem construct b2-d and a free a4 subunit exhibited large steroid responses. We propose that free a4, b2, and d subunits assemble in different configurations with distinct properties in oocytes and HEK cells, and that subunit linkage can overcome the expression system-dependent preferential assembly of free subunits. Hippocampal neurons transfected with a4 and the picrotoxin-resistant d(T269Y) subunit showed large responses to alfaxalone in the presence of picrotoxin, suggesting that a4bd receptors may assemble in a similar configuration in neurons and oocytes.

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Rescue of deficient amygdala tonic γ‐aminobutyric acidergic currents in the Fmr^–/y mouse model of fragile X syndrome by a novel γ‐aminobutyric acid type A receptor‐positive allosteric modulator

Martin

Martínez-Botella

Loya

et al. 2015

J of Neuroscience Research

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Alterations in the ratio of excitatory to inhibitory transmission are emerging as a common component of many nervous system disorders, including autism spectrum disorders (ASDs). Tonic γ-aminobutyric acidergic (GABAergic) transmission provided by peri- and extrasynaptic GABA type A (GABAA) receptors powerfully controls neuronal excitability and plasticity and, therefore, provides a rational therapeutic target for normalizing hyperexcitable networks across a variety of disorders, including ASDs. Our previous studies revealed tonic GABAergic deficits in principal excitatory neurons in the basolateral amygdala (BLA) in the Fmr1−/y knockout (KO) mouse model fragile X syndrome. To correct amygdala deficits in tonic GABAergic neurotransmission in Fmr1−/y KO mice, we developed a novel positive allosteric modulator of GABAA receptors, SGE-872, based on endogenously active neurosteroids. This study shows that SGE-872 is nearly as potent and twice as efficacious for positively modulating GABAA receptors as its parent molecule, allopregnanolone. Furthermore, at submicromolar concentrations (≤1 µM), SGE-872 is selective for tonic, extrasynaptic α4β3δ-containing GABAA receptors over typical synaptic α1β2γ2 receptors. We further find that SGE-872 strikingly rescues the tonic GABAergic transmission deficit in principal excitatory neurons in the Fmr1−/y KO BLA, a structure heavily implicated in the neuropathology of ASDs. Therefore, the potent and selective action of SGE-872 on tonic GABAA receptors containing α4 subunits may represent a novel and highly useful therapeutic avenue for ASDs and related disorders involving hyperexcitability of neuronal networks.

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Pharmacological characterization of a novel positive modulator at α4β3δ-containing extrasynaptic GABAA receptors

Cited by 29 publications

References 33 publications

A study of subunit selectivity, mechanism and site of action of the delta selective compound 2 (DS2) at human recombinant and rodent native GABA_A receptors

A study of subunit selectivity, mechanism and site of action of the delta selective compound 2 (DS2) at human recombinant and rodent native GABA_A receptors

γ-Aminobutyric Acid Type A α4, β2, and δ Subunits Assemble to Produce More Than One Functionally Distinct Receptor Type

Rescue of deficient amygdala tonic γ‐aminobutyric acidergic currents in the Fmr^–/y mouse model of fragile X syndrome by a novel γ‐aminobutyric acid type A receptor‐positive allosteric modulator

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Pharmacological characterization of a novel positive modulator at α4β3δ-containing extrasynaptic GABAA receptors

Cited by 29 publications

References 33 publications

A study of subunit selectivity, mechanism and site of action of the delta selective compound 2 (DS2) at human recombinant and rodent native GABAA receptors

A study of subunit selectivity, mechanism and site of action of the delta selective compound 2 (DS2) at human recombinant and rodent native GABAA receptors

γ-Aminobutyric Acid Type A α4, β2, and δ Subunits Assemble to Produce More Than One Functionally Distinct Receptor Type

Rescue of deficient amygdala tonic γ‐aminobutyric acidergic currents in the Fmr–/y mouse model of fragile X syndrome by a novel γ‐aminobutyric acid type A receptor‐positive allosteric modulator

Contact Info

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Resources

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A study of subunit selectivity, mechanism and site of action of the delta selective compound 2 (DS2) at human recombinant and rodent native GABA_A receptors

A study of subunit selectivity, mechanism and site of action of the delta selective compound 2 (DS2) at human recombinant and rodent native GABA_A receptors

Rescue of deficient amygdala tonic γ‐aminobutyric acidergic currents in the Fmr^–/y mouse model of fragile X syndrome by a novel γ‐aminobutyric acid type A receptor‐positive allosteric modulator