ERK1/2-Dependent Phosphorylation of GABAB1(S867/T872), Controlled by CaMKIIβ, Is Required for GABAB Receptor Degradation under Physiological and Pathological Conditions

GABA(B) receptor-mediated inhibition is indispensable for maintaining a healthy neuronal excitation/inhibition balance. Many neurological diseases are associated with a disturbed excitation/inhibition balance and downregulation of GABA(B) receptors due to enhanced sorting of the receptors to lysosomal degradation. A key event triggering the downregulation of the receptors is the phosphorylation of S867 in the GABA(B1) subunit mediated by CaMKII beta. Interestingly, close to S867 in GABA(B1) exists another phosphorylation site, T872. Therefore, the question arose as to whether phosphorylation of T872 is involved in downregulating the receptors and whether phosphorylation of this site is also mediated by CaMKII beta or by another protein kinase. Here, we show that mutational inactivation of T872 in GABA(B1) prevented the degradation of the receptors in cultured neurons. We found that, in addition to CaMKII beta, also ERK1/2 is involved in the degradation pathway of GABA(B) receptors under physiological and ischemic conditions. In contrast to our previous view, CaMKII beta does not appear to directly phosphorylate S867. Instead, the data support a mechanism in which CaMKII beta activates ERK1/2, which then phosphorylates S867 and T872 in GABA(B1). Blocking ERK activity after subjecting neurons to ischemic stress completely restored downregulated GABAB receptor expression to normal levels. Thus, preventing ERK1/2-mediated phosphorylation of S867/T872 in GABA(B1) is an opportunity to inhibit the pathological downregulation of the receptors after ischemic stress and is expected to restore a healthy neuronal excitation/inhibition balance.