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http://purl.uniprot.org/citations/32484592http://www.w3.org/1999/02/22-rdf-syntax-ns#typehttp://purl.uniprot.org/core/Journal_Citation
http://purl.uniprot.org/citations/32484592http://www.w3.org/2000/01/rdf-schema#comment"

Background and purpose

The δ-subunit-containing GABAA receptors, α4 β1 δ and α4 β3 δ, in dentate gyrus granule cells (DGGCs) are known to exhibit both spontaneous channel openings (i.e. constitutive activity) and agonist-induced current. The functional implications of spontaneous gating are unclear. In this study, we tested the hypothesis that constitutively active α4 β1/3 δ receptors limit agonist efficacy.

Experimental approach

Whole-cell electrophysiological recordings of adult male rat and mouse hippocampal DGGCs were used to characterize known agonists and antagonists at δ-subunit-containing GABAA receptors. To separate constitutive and agonist-induced currents, different recording conditions were employed.

Key results

Recordings at either 24°C or 34°C, including the PKC autoinhibitory peptide (19-36) intracellularly, removed spontaneous gating by GABAA receptors. In the absence of spontaneous gating, DGGCs responded to the α4 β1/3 δ orthosteric agonist Thio-THIP with a four-fold increased efficacy relative to recording conditions favouring constitutive activity. Surprisingly, the neutral antagonist gabazine was unable to antagonize the current by Thio-THIP. Furthermore, a current was elicited by gabazine alone only when the constitutive current was silenced (EC50 2.1 μM). The gabazine-induced current was inhibited by picrotoxin, potentiated by DS2, completely absent in δ-/- mice and reduced in β1 -/- mice, but could not be replicated in human α4 β1/3 δ receptors expressed heterologously in HEK cells.

Conclusion and implications

Kinase activity infers spontaneous gating in α4 β1/3 δ receptors in DGGCs. This significantly limits the efficacy of GABAA agonists and has implications in pathologies involving aberrant excitability caused by phosphorylation (e.g. addiction and epilepsy). In such cases, the efficacy of δ-preferring GABAA ligands may be reduced."xsd:string
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http://purl.uniprot.org/citations/32484592http://purl.uniprot.org/core/author"Scholze P."xsd:string
http://purl.uniprot.org/citations/32484592http://purl.uniprot.org/core/author"Wellendorph P."xsd:string
http://purl.uniprot.org/citations/32484592http://purl.uniprot.org/core/author"Frolund B."xsd:string
http://purl.uniprot.org/citations/32484592http://purl.uniprot.org/core/author"Krall J."xsd:string
http://purl.uniprot.org/citations/32484592http://purl.uniprot.org/core/author"Dalby N.O."xsd:string
http://purl.uniprot.org/citations/32484592http://purl.uniprot.org/core/author"Leurs U."xsd:string
http://purl.uniprot.org/citations/32484592http://purl.uniprot.org/core/author"Falk-Petersen C.B."xsd:string
http://purl.uniprot.org/citations/32484592http://purl.uniprot.org/core/date"2020"xsd:gYear
http://purl.uniprot.org/citations/32484592http://purl.uniprot.org/core/name"Br J Pharmacol"xsd:string
http://purl.uniprot.org/citations/32484592http://purl.uniprot.org/core/pages"3975-3990"xsd:string
http://purl.uniprot.org/citations/32484592http://purl.uniprot.org/core/title"Silencing of spontaneous activity at alpha4beta1/3delta GABApisub>Api/sub> receptors in hippocampal granule cells reveals different ligand pharmacology."xsd:string
http://purl.uniprot.org/citations/32484592http://purl.uniprot.org/core/volume"177"xsd:string
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