Dataset Information

Towards functional selectivity for α6β3γ2 GABA_A receptors: a series of novel pyrazoloquinolinones.

ABSTRACT:

Background and purpose

The GABA_A receptors are ligand-gated ion channels, which play an important role in neurotransmission. Their variety of binding sites serves as an appealing target for many clinically relevant drugs. Here, we explored the functional selectivity of modulatory effects at specific extracellular α+/β- interfaces, using a systematically varied series of pyrazoloquinolinones.

Experimental approach

Recombinant GABA_A receptors were expressed in Xenopus laevis oocytes and modulatory effects on GABA-elicited currents by the newly synthesized and reference compounds were investigated by the two-electrode voltage clamp method.

Key results

We identified a new compound which, to the best of our knowledge, shows the highest functional selectivity for positive modulation at α6β3γ2 GABA_A receptors with nearly no residual activity at the other αxβ3γ2 (x = 1-5) subtypes. This modulation was independent of affinity for α+/γ- interfaces. Furthermore, we demonstrated for the first time a compound that elicits a negative modulation at specific extracellular α+/β- interfaces.

Conclusion and implications

These results constitute a major step towards a potential selective positive modulation of certain α6-containing GABA_A receptors, which might be useful to elicit their physiological role. Furthermore, these studies pave the way towards insights into molecular principles that drive positive versus negative allosteric modulation of specific GABA_A receptor isoforms.

SUBMITTER: Treven M

PROVIDER: S-EPMC5773961 | biostudies-literature |

REPOSITORIES: biostudies-literature

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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

Towards functional selectivity for α6β3γ2 GABA_A receptors: a series of novel pyrazoloquinolinones.

Background and purpose

Experimental approach

Key results

Conclusion and implications

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets

Dataset Information

Towards functional selectivity for α6β3γ2 GABAA receptors: a series of novel pyrazoloquinolinones.

Background and purpose

Experimental approach

Key results

Conclusion and implications

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets

Towards functional selectivity for α6β3γ2 GABA_A receptors: a series of novel pyrazoloquinolinones.