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ERK1/2-Dependent Phosphorylation of GABA$_{B1}$(S867/T872), Controlled by CaMKIIβ, Is Required for GABA$_{B}$ Receptor Degradation under Physiological and Pathological Conditions


Bhat, Musadiq A; Grampp, Thomas; Benke, Dietmar (2023). ERK1/2-Dependent Phosphorylation of GABA$_{B1}$(S867/T872), Controlled by CaMKIIβ, Is Required for GABA$_{B}$ Receptor Degradation under Physiological and Pathological Conditions. International Journal of Molecular Sciences, 24(17):13436.

Abstract

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 CaMKIIβ. 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 CaMKIIβ 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 CaMKIIβ, also ERK1/2 is involved in the degradation pathway of GABA$_{B}$ receptors under physiological and ischemic conditions. In contrast to our previous view, CaMKIIβ does not appear to directly phosphorylate S867. Instead, the data support a mechanism in which CaMKIIβ activates ERK1/2, which then phosphorylates S867 and T872 in GABA$_{B1}$. Blocking ERK activity after subjecting neurons to ischemic stress completely restored downregulated GABA$_{B}$ 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.

Abstract

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 CaMKIIβ. 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 CaMKIIβ 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 CaMKIIβ, also ERK1/2 is involved in the degradation pathway of GABA$_{B}$ receptors under physiological and ischemic conditions. In contrast to our previous view, CaMKIIβ does not appear to directly phosphorylate S867. Instead, the data support a mechanism in which CaMKIIβ activates ERK1/2, which then phosphorylates S867 and T872 in GABA$_{B1}$. Blocking ERK activity after subjecting neurons to ischemic stress completely restored downregulated GABA$_{B}$ 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.

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Item Type:Journal Article, refereed, original work
Communities & Collections:04 Faculty of Medicine > Institute of Pharmacology and Toxicology
07 Faculty of Science > Institute of Pharmacology and Toxicology
Dewey Decimal Classification:570 Life sciences; biology
610 Medicine & health
Scopus Subject Areas:Physical Sciences > Catalysis
Life Sciences > Molecular Biology
Physical Sciences > Spectroscopy
Physical Sciences > Computer Science Applications
Physical Sciences > Physical and Theoretical Chemistry
Physical Sciences > Organic Chemistry
Physical Sciences > Inorganic Chemistry
Language:English
Date:30 August 2023
Deposited On:26 Sep 2023 12:24
Last Modified:29 Jun 2024 01:38
Publisher:MDPI Publishing
ISSN:1422-0067
OA Status:Gold
Free access at:Publisher DOI. An embargo period may apply.
Publisher DOI:https://doi.org/10.3390/ijms241713436
PubMed ID:37686242
Other Identification Number:PMCID: PMC10488028
  • Content: Published Version
  • Language: English
  • Licence: Creative Commons: Attribution 4.0 International (CC BY 4.0)