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

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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 is 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 pharmacologically 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, but 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. In turn this significantly limits the efficacy of GABAA agonists. This has implications in pathologies involving aberrant excitability caused by phosphorylation (e.g. addiction and epilepsy). In such cases the efficacy of delta-preferring GABAA ligands may be reduced.

TidsskriftBritish Journal of Pharmacology
Udgave nummer17
Sider (fra-til)3975-3990
StatusUdgivet - 2020

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