| First Author | Dalby NO | Year | 2020 |
| Journal | Br J Pharmacol | Volume | 177 |
| Issue | 17 | Pages | 3975-3990 |
| PubMed ID | 32484592 | Mgi Jnum | J:302682 |
| Mgi Id | MGI:6509358 | Doi | 10.1111/bph.15146 |
| Citation | Dalby NO, et al. (2020) Silencing of spontaneous activity at alpha4beta1/3delta GABAA receptors in hippocampal granule cells reveals different ligand pharmacology. Br J Pharmacol 177(17):3975-3990 |
| abstractText | BACKGROUND AND PURPOSE: The delta-subunit-containing GABAA receptors, alpha4 beta1 delta and alpha4 beta3 delta, 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 alpha4 beta1/3 delta 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 delta-subunit-containing GABAA receptors. To separate constitutive and agonist-induced currents, different recording conditions were employed. KEY RESULTS: Recordings at either 24 degrees C or 34 degrees 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 alpha4 beta1/3 delta 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 muM). The gabazine-induced current was inhibited by picrotoxin, potentiated by DS2, completely absent in delta(-/-) mice and reduced in beta1 (-/-) mice, but could not be replicated in human alpha4 beta1/3 delta receptors expressed heterologously in HEK cells. CONCLUSION AND IMPLICATIONS: Kinase activity infers spontaneous gating in alpha4 beta1/3 delta 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 delta-preferring GABAA ligands may be reduced. |
