Differential Regulation of GABAB Receptor Trafficking by Different Modes of N-methyl-d-aspartate (NMDA) Receptor Signaling

Abstract

Background: Heterodimerization of GABAB1 and GABAB2 subunits is required for functional GABABRs.Results: GABABR subunits are differentially regulated by activation of synaptic or extrasynaptic NMDARs.Conclusion: GABABR trafficking and function is regulated by NMDARs.Significance: GABABRs are potential targets for treating diseases such as stroke and cerebral ischemia.

Ca2+/Calmodulin-Dependent Protein Kinase II (CaMKII) β-Dependent Phosphorylation of GABAB1 Triggers Lysosomal Degradation of GABAB Receptors via Mind Bomb-2 (MIB2)-Mediated Lys-63-Linked Ubiquitination

“…Sorting the receptors to recycling or degradation must be precisely regulated in order to provide the required number of cell surface receptors for signal transduction under a given physiological condition. However, after prolonged activation of glutamate receptors, GABA B receptors are rapidly downregulated by shifting the recycling/degradation balance towards lysosomal degradation [30][31][32]. This downregulation of GABA B receptors critically depends on CaMKII-mediated phosphorylation of GABA B1 on Ser-867 [29] as well as on Lys-63-linked ubiquitination of GABA B1 mediated by the E3 ligase MIB2 [17].…”

“…In addition to CaMKIIβ controlling cell surface GABA B receptor expression under normal physiological conditions, it rapidly downregulates the receptors upon sustained activation of glutamate receptors [29][30][31][32], a pathological condition that occurs in cerebral ischemia and leads to excitotoxic cell death [42,43]. Downregulation of GABA B receptors is triggered by increased Ca 2+ influx through NMDA receptors and voltagegated Ca 2+ channels [30], leading to enhanced CaMKIImediated phosphorylation of GABA B1 on Ser867 [29].…”

“…Sustained activation of glutamate receptors, which occurs in cerebral ischemia, downregulates GABA B receptors by preferentially sorting constitutively internalized receptors to lysosomes for degradation instead of recycling them to the cell surface [29][30][31][32]. Phosphorylation of GABA B1 at Ser-867 by CaMKII plays a key role in this mechanism [29].…”

Neuroadaptations of presynaptic and postsynaptic GABAB receptor function in the paraventricular nucleus in response to chronic unpredictable stress

“…The current density (normalized by cell capacitance) of baclofen‐induced currents was significantly smaller in CUMS‐exposed rats than in unstressed rats (Figure ). Glutamate application led to GABA B receptor endocytosis through activation of NMDA receptors (Guetg et al , ; Kantamneni et al , ), and the glutamate signal was increased in the PVN in chronic stress (Ziegler et al , ). Thus, we tested the effects of enhanced NMDA receptor activity on GABA B receptor function in the PVN in CUMS rats.…”

“…We found that pretreatment of the brain slices with NMDA receptor antagonist AP5 for a short time led to recovered baclofen‐induced currents in PVN‐CRH neurons in CUMS rats. Because activation of NMDA receptors induces internalization of GABA B receptors (Guetg et al , ; Kantamneni et al , ), it is likely that AP5 treatment blunted the internalization of GABA B receptor to preserve the membrane GABA B receptor in PVN‐CRH neurons. These data suggest that enhanced NMDA receptor activity in chronic stress is involved in the blunted GABA B receptor function.…”