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The G protein-coupled GABA B receptors, constituted from GABA B1 and GABA B2 subunits, are important regulators of neuronal excitability by mediating long-lasting inhibition. One factor that determines receptor availability and thereby the strength of inhibition is regulated protein degradation. GABA B receptors are constitutively internalized from the plasma membrane and are either recycled to the cell surface or degraded in lysosomes. Lys-63-linked ubiquitination mediated by the E3 ligase Mind bomb-2 (MIB2) is the signal that sorts GABA B receptors to lysosomes. However, it is unknown how Lys-63-linked ubiquitination and thereby lysosomal degradation of the receptors is regulated. Here, we show that Ca 2+ /calmodulin-dependent protein kinase II (CaMKII) promotes MIB2-mediated Lys-63-linked ubiquitination of GABA B receptors. We found that inhibition of CaMKII in cultured rat cortical neurons increased cell surface GABA B receptors, whereas overexpression of CaMKIIβ, but not CaMKIIα, decreased receptor levels. This effect was conveyed by Lys-63-linked ubiquitination of GABA B1 at multiple sites mediated by the E3 ligase MIB2. Inactivation of the CaMKII phosphorylation site on GABA B1 (Ser-867) strongly reduced Lys-63-linked ubiquitination of GABA B receptors and increased their cell surface expression, whereas the phosphomimetic mutant GABA B1 (S867D) exhibited strongly increased Lys-63-linked ubiquitination and reduced cell surface expression. Finally, triggering lysosomal degradation of GABA B receptors by sustained activation of glutamate receptors, a condition occurring in brain ischemia, was accompanied with a massive increase of GABA B1 (Ser-867) phosphorylation-dependent Lys-63-linked ubiquitination of GABA B receptors. These findings indicate that CaMKIIβ-dependent Lys-63-linked ubiquitination of GABA B1 at multiple sites controls sorting of GABA B receptors to lysosomes for degradation under physiological and pathological condition.

molecular neurobiology

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