Activity-dependent phosphorylation of GABAA receptors regulates receptor insertion and tonic current

• Published in: The EMBO journal Vol. 31; no. 13; pp. 2937 - 2951
• Main Authors: Saliba, Richard S, Kretschmannova, Karla, Moss, Stephen J
• Format: Journal Article
• Language: English
• Published: Chichester, UK John Wiley & Sons, Ltd 29.06.2012; Nature Publishing Group UK; Springer Nature B.V; Nature Publishing Group
• Subjects: Animals; Calcium - metabolism; Calcium Channels, L-Type - physiology; Calcium-Calmodulin-Dependent Protein Kinase Type 2 - metabolism; CaMKII; EMBO27; exocytosis; GABAA receptors; Hippocampus - physiology; Homeostasis; Male; Mice; Mice, Inbred C57BL; Molecular biology; Neurons - physiology; Neurosciences; Phosphorylation; Receptors, GABA-A - physiology; tonic inhibition; exocytosis; CaMKII; tonic inhibition; phosphorylation; GABAA receptors
• ISSN: 0261-4189; 1460-2075; 1460-2075
• DOI: 10.1038/emboj.2012.109

The expression of GABA A receptors and the efficacy of GABAergic neurotransmission are subject to adaptive compensatory regulation as a result of changes in neuronal activity. Here, we show that activation of L‐type voltage‐gated Ca 2+ channels (VGCCs) leads to Ca 2+ /calmodulin‐dependent protein kinase II (CaMKII) phosphorylation of S383 within the β3 subunit of the GABA A receptor. Consequently, this results in rapid insertion of GABA A receptors at the cell surface and enhanced tonic current. Furthermore, we demonstrate that acute changes in neuronal activity leads to the rapid modulation of cell surface numbers of GABA A receptors and tonic current, which are critically dependent on Ca 2+ influx through L‐type VGCCs and CaMKII phosphorylation of β3S383. These data provide a mechanistic link between activity‐dependent changes in Ca 2+ influx through L‐type channels and the rapid modulation of GABA A receptor cell surface numbers and tonic current, suggesting a homeostatic pathway involved in regulating neuronal intrinsic excitability in response to changes in activity. Neuronal activity‐induced activation of Ca 2+ channels results in CaMKII‐mediated phosphorylation of GABAA receptors, leading to the rapid insertion of GABAA receptors at the cell surface and their persistent activation.