AUTHOR=Bhat Musadiq A. , Esmaeili Abolghasem , Neumann Elena , Balakrishnan Karthik , Benke Dietmar 

TITLE=Targeting the Interaction of GABAB Receptors With CHOP After an Ischemic Insult Restores Receptor Expression and Inhibits Progressive Neuronal Death

JOURNAL=Frontiers in Pharmacology

VOLUME=13

YEAR=2022

URL=https://www.frontiersin.org/journals/pharmacology/articles/10.3389/fphar.2022.870861

DOI=10.3389/fphar.2022.870861

ISSN=1663-9812

ABSTRACT=<p>GABA<sub>B</sub> receptors control neuronal excitability via slow and prolonged inhibition in the central nervous system. One important function of GABA<sub>B</sub> receptors under physiological condition is to prevent neurons from shifting into an overexcitation state which can lead to excitotoxic death. However, under ischemic conditions, GABA<sub>B</sub> receptors are downregulated, fostering over-excitation and excitotoxicity. One mechanism downregulating GABA<sub>B</sub> receptors is mediated via the interaction with the endoplasmic reticulum (ER) stress-induced transcription factor CHOP. In this study, we investigated the hypothesis that preventing the interaction of CHOP with GABA<sub>B</sub> receptors after an ischemic insult restores normal expression of GABA<sub>B</sub> receptors and reduces neuronal death. For this, we designed an interfering peptide (R2-Pep) that restored the CHOP-induced downregulation of cell surface GABA<sub>B</sub> receptors in cultured cortical neurons subjected to oxygen and glucose deprivation (OGD). Administration of R2-Pep after OGD restored normal cell surface expression of GABA<sub>B</sub> receptors as well as GABA<sub>B</sub> receptor-mediated inhibition. As a result, R2-Pep reduced enhanced neuronal activity and inhibited progressive neuronal death in OGD stressed cultures. Thus, targeting diseases relevant protein-protein interactions might be a promising strategy for developing highly specific novel therapeutics.</p>