Proteasomal Degradation of γ-Aminobutyric AcidB Receptors Is Mediated by the Interaction of the GABAB2 C Terminus with the Proteasomal ATPase Rtp6 and Regulated by Neuronal Activity

Background: The expression level of GABA(B) receptors is controlled by proteasomal degradation. Results: Proteasomal degradation of GABA(B) receptors is mediated by interaction with Rpt6 and modulated by neuronal activity. Conclusion: The level of neuronal activity regulates via proteasomal degradation the ER pool of GABA(B) receptor competent for forward trafficking. Significance: This mechanism might contribute to homeostatic neuronal plasticity. Regulation of cell surface expression of neurotransmitter receptors is crucial for determining synaptic strength and plasticity, but the underlying mechanisms are not well understood. We previously showed that proteasomal degradation of GABA(B) receptors via the endoplasmic reticulum (ER)-associated protein degradation (ERAD) machinery determines the number of cell surface GABA(B) receptors and thereby GABA(B) receptor-mediated neuronal inhibition. Here, we show that proteasomal degradation of GABA(B) receptors requires the interaction of the GABA(B2) C terminus with the proteasomal AAA-ATPase Rpt6. A mutant of Rpt6 lacking ATPase activity prevented degradation of GABA(B) receptors but not the removal of Lys(48)-linked ubiquitin from GABA(B2). Blocking ERAD activity diminished the interaction of Rtp6 with GABA(B) receptors resulting in increased total as well as cell surface expression of GABA(B) receptors. Modulating neuronal activity affected proteasomal activity and correspondingly the interaction level of Rpt6 with GABA(B2). This resulted in altered cell surface expression of the receptors. Thus, neuronal activity-dependent proteasomal degradation of GABA(B) receptors by the ERAD machinery is a potent mechanism regulating the number of GABA(B) receptors available for signaling and is expected to contribute to homeostatic neuronal plasticity.