• CaMKII;
  • exocytosis;
  • GABAA receptors;
  • phosphorylation;
  • tonic inhibition

The expression of GABAA 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 Ca2+ channels (VGCCs) leads to Ca2+/calmodulin-dependent protein kinase II (CaMKII) phosphorylation of S383 within the β3 subunit of the GABAA receptor. Consequently, this results in rapid insertion of GABAA 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 GABAA receptors and tonic current, which are critically dependent on Ca2+ influx through L-type VGCCs and CaMKII phosphorylation of β3S383. These data provide a mechanistic link between activity-dependent changes in Ca2+ influx through L-type channels and the rapid modulation of GABAA receptor cell surface numbers and tonic current, suggesting a homeostatic pathway involved in regulating neuronal intrinsic excitability in response to changes in activity.