Silencing of spontaneous activity at α4β1/3δ GABA A receptors in hippocampal granule cells reveals different ligand pharmacology.

Autor: Dalby NO; Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark., Falk-Petersen CB; Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark., Leurs U; Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark., Scholze P; Department of Pathobiology of the Nervous System, Center for Brain Research, Medical University of Vienna, Vienna, Austria., Krall J; Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark., Frølund B; Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark., Wellendorph P; Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
Jazyk: angličtina
Zdroj: British journal of pharmacology [Br J Pharmacol] 2020 Sep; Vol. 177 (17), pp. 3975-3990. Date of Electronic Publication: 2020 Jul 15.
DOI: 10.1111/bph.15146
Abstrakt: Background and Purpose: The δ-subunit-containing GABA A receptors, α 4 β 1 δ and α 4 β 3 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 α 4 β 1/3 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 GABA A 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 GABA A receptors. In the absence of spontaneous gating, DGGCs responded to the α 4 β 1/3 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 (EC 50 2.1 μM). The gabazine-induced current was inhibited by picrotoxin, potentiated by DS2, completely absent in δ -/- mice and reduced in β 1 -/- mice, but could not be replicated in human α 4 β 1/3 δ receptors expressed heterologously in HEK cells.
Conclusion and Implications: Kinase activity infers spontaneous gating in α 4 β 1/3 δ receptors in DGGCs. This significantly limits the efficacy of GABA A 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 GABA A ligands may be reduced.
(© 2020 The British Pharmacological Society.)
Databáze: MEDLINE
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