The point mutation γ2F77I changes the potency and efficacy of benzodiazepine site ligands in different GABAA receptor subtypes

Ramerstorfer, Joachim; Furtmüller, Roman; Vogel, Elisabeth; Huck, Sigismund; Sieghart, Werner

doi:10.1016/j.ejphar.2010.03.015

Cited by 45 publications

(69 citation statements)

References 38 publications

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“…Flumazenil, a potentiator of ␣4, ␤3, and ␥2 subunitcontaining GABA A receptors (Ramerstorfer et al, 2010), failed to prolong IPSC decay in either condition, excluding a role for the ␣4 subunit (data not shown). Diazepam acts as a positive allosteric modulator at the benzodiazepine site of ␣1-3-containing or ␣5-containing GABA A receptors.…”

Section: Pharmacology Of Inhibitory Synaptic Connections Between Msnsmentioning

confidence: 99%

Dopamine D2 Receptors Regulate Collateral Inhibition between Striatal Medium Spiny Neurons

Lalchandani

Goes

Partridge

et al. 2013

Journal of Neuroscience

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Section: Pharmacology Of Inhibitory Synaptic Connections Between Msnsmentioning

confidence: 99%

Dopamine D2 Receptors Regulate Collateral Inhibition between Striatal Medium Spiny Neurons

Lalchandani

Goes

Partridge

et al. 2013

Journal of Neuroscience

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“…Xenopus laevis oocytes (Nasco, Fort Atkinson, WI) were coinjected with synthesized rat GABA A R subunit messenger RNAs (each a subunit [1][2][3][4][5][6] with b3 and g2, or a4 with b3 and d), as described previously (17), to express GABA A Rs of prescribed subunit composition. Concentration ranges of CMD-45 or XHe-III-74 were applied for 30 seconds before the addition of a 3% maximal effective concentration (EC 3 ) of GABA, and voltage-clamp current recordings were performed at a holding potential of 260 mV.…”

Section: Oocyte Electrophysiological Studiesmentioning

confidence: 99%

Targeting the γ-Aminobutyric Acid A Receptor α4 Subunit in Airway Smooth Muscle to Alleviate Bronchoconstriction

Yocum

Gallos

Zhang

et al. 2016

Am J Respir Cell Mol Biol

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We previously demonstrated that airway smooth muscle (ASM) cells express g-aminobutyric acid A receptors (GABA A Rs), and that GABA A R agonists acutely relax ASM. Among the GABA A R a subunits, human ASM cells express only a4 and a5, providing the opportunity for selective pharmacologic targeting. Novel GABA A R-positive allosteric modulators designed for enhanced a4/a6 subunit selectivity were synthesized using iterative computational analyses (CMD-45 and XHe-III-74). Studies using oocyte heterologous expression systems confirmed that CMD-45 and XHe-III-74 led to significantly greater augmentation of currents induced by a 3% maximal effective concentration (EC 3 ) of GABA [EC 3 ]-induced currents in oocytes expressing a4 or a6 subunits (along with b3 and g2) compared with other a subunits. CMD-45 and XHe-III-74 also led to greater ex vivo relaxation of contracted wild-type mouse tracheal rings compared with tracheal rings from GABA A R a4 subunit (Gabra4) knockout mice. Furthermore, CMD-45 and XHe-III-74 significantly relaxed precontracted human ASM ex vivo, and, at a low concentration, both ligands led to a significant leftward shift in albuterolmediated ASM relaxation. In vivo, inhaled XHe-III-74 reduced respiratory system resistance in an asthmatic mouse model. Pretreatment of human ASM cells with CMD-45 and XHe-III-74 inhibited histamine-induced increases in intracellular calcium concentrations in vitro, an effect that was lost when calcium was omitted from the extracellular buffer, suggesting that inhibition of calcium influx due to alterations in plasma membrane potential may play a role in the mechanism of ASM relaxation. Selective targeting of the GABA A R a4 subunit with inhaled ligands may be a novel therapeutic pathway to treat bronchoconstriction, while avoiding sedative central nervous system effects, which are largely mediated by a1-3 subunit-containing GABA A Rs in the brain.

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“…In vitro transcription of mRNA was based on the cDNA expression vectors encoding for GABAA receptor subunits a1, b3 and g2 (all from rat) (Ramerstorfer et al, 2010). After linearizing the cDNA vectors with appropriate restriction endonucleases, capped transcripts were produced using the mMESSAGE mMACHINE® T7 transcription kit (Ambion, TX, USA).…”

Section: Two Electrode Voltage Clamp (Tev)mentioning

confidence: 99%

Identification of novel positive allosteric modulators and null modulators at the GABA_A receptor α+β− interface

Varagić

Wimmer

Schnürch

et al. 2013

British J Pharmacology

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105

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BACKGROUND AND PURPOSEGABAA receptors are the major inhibitory neurotransmitter receptors in the mammalian brain and the target of many clinically important drugs interacting with different binding sites. Recently, we demonstrated that CGS 9895 (2-(4-methoxyphenyl)-2H-pyrazolo [4,3-c]quinolin-3(5H)-one) acts as a null modulator (antagonist) at the high affinity benzodiazepine binding site, but in addition elicits a strong enhancement of GABA-induced currents via a novel drug binding site at the extracellular a+b-interface. Here, we investigated 32 structural analogues of CGS 9895 for their ability to mediate their effects via the a1+b3-interface of GABAA receptors. EXPERIMENTAL APPROACHGABAA receptors were expressed in Xenopus laevis oocytes and investigated by the two-electrode voltage clamp method. KEY RESULTSWe not only identified compounds with higher efficacy/potency than CGS 9895 for stimulating GABA-induced currents via the a1+b3-binding site, but also discovered compounds acting as null modulators at this site. Most of the compounds also acted as null modulators via the benzodiazepine binding site of GABAA receptors. But some of the positive allosteric modulators or null modulators exclusively exerted their action via the a+b-binding site. CONCLUSION AND IMPLICATIONSPyrazoloquinolinones and pyrazolopyridinones represent the first prototype of drug candidates mediating benzodiazepine like modulatory effects via the a+b-interface of GABAA receptors. The discovery of null modulators acting as inhibitors of the plus modulators provides a highly useful tool for the discovery of additional classes of compounds that can modulate GABAA receptors via this site, which may lead to novel therapeutic principles. LINKED ARTICLEThis article is accompanied by Varagic et al.,

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The point mutation γ2F77I changes the potency and efficacy of benzodiazepine site ligands in different GABAA receptor subtypes

Cited by 45 publications

References 38 publications

Dopamine D2 Receptors Regulate Collateral Inhibition between Striatal Medium Spiny Neurons

Dopamine D2 Receptors Regulate Collateral Inhibition between Striatal Medium Spiny Neurons

Targeting the γ-Aminobutyric Acid A Receptor α4 Subunit in Airway Smooth Muscle to Alleviate Bronchoconstriction

Identification of novel positive allosteric modulators and null modulators at the GABA_A receptor α+β− interface

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The point mutation γ2F77I changes the potency and efficacy of benzodiazepine site ligands in different GABAA receptor subtypes

Cited by 45 publications

References 38 publications

Dopamine D2 Receptors Regulate Collateral Inhibition between Striatal Medium Spiny Neurons

Dopamine D2 Receptors Regulate Collateral Inhibition between Striatal Medium Spiny Neurons

Targeting the γ-Aminobutyric Acid A Receptor α4 Subunit in Airway Smooth Muscle to Alleviate Bronchoconstriction

Identification of novel positive allosteric modulators and null modulators at the GABAA receptor α+β− interface

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Identification of novel positive allosteric modulators and null modulators at the GABA_A receptor α+β− interface