Dr. Jinwei Zhang is a Medicine Professor and the Research Center of Chemical Kinomics Director at the State Key Laboratory of Chemical Biology, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences. Additionally, he serves as a Principal Investigator in Medicine at the University of Exeter Medical School, UK. His research focuses on ion channels, transporters, and signaling pathways associated with human diseases, such as stroke regulated by WNK-SPAK/OSR1-KCC2/NKCC1 and hypertension regulated by WNK-SPAK/OSR1-NCC. Dr. Zhang employs genetic mouse models, small molecules, CRISPR/Cas9 gene-editing technologies, and electrophysiology to elucidate and target ion transporters, kinases, and protein-protein interactions facilitating the discovery and validation of new potential drug targets. He is internationally recognized for his expertise in cellular chloride homeostasis, cell volume regulation, and drug discovery. Dr. Zhang has authored over 100 articles in reputable journals, including Cell, Nature Medicine, Cell Metabolism, Neuron, Nature Communications, EMBO Molecular Medicine, Science Signaling, and Human Molecular Genetics. His work has garnered over 3400 citations, with an H-index of 30. Dr. Zhang holds editorial roles as an Associate Editor for Frontiers in Pharmacology, Microbiology, and Physiology. He also serves as the Editor in Chief for the Journal of Modern Biology and Drug Discovery. Actively engaged in the scientific community, he is a member of the editorial boards of 40 scientific journals, including Medicinal Research Reviews. He also acts as a reviewer for over 60 scientific journals, including Chem. Dr. Zhang has completed reviews for more than 140 manuscripts.
The transporter KCC2 (SLC12A5), responsible for extruding chloride ions (Cl-), plays a crucial role in modulating GABAA receptor signaling by influencing neuronal Cl- homeostasis. Prior investigations have revealed the downregulation of KCC2 in epileptic patients and various animal models of epilepsy. Our findings unveil a dual phosphorylation mechanism involving Thr906 and Thr1007 within the intracellular carboxyl (C)-terminal domain of KCC2. This phosphorylation, facilitated by the Cl--sensitive WNK-SPAK serine-threonine protein kinase complex, sustains the depolarizing effect of GABA in immature neurons, counteracting KCC2's Cl- extrusion capability. GABAAR-mediated inhibition confines KCC2 to the plasma membrane, whereas inhibiting this process reduces KCC2 surface expression by enhancing lateral diffusion and endocytosis of the transporter. This intricate mechanism utilizes Cl- as an intracellular secondary messenger, relying on WNK1-mediated phosphorylation of KCC2 at threonines 906 and 1007 in response to Cl- levels. We propose that this mechanism dynamically contributes to synaptic inhibition homeostasis by promptly adjusting neuronal [Cl-]i based on GABAAR activity. Our study also reveals this signaling pathway's rapid and substantial activation in an acute epilepsy model. This implies that dephosphorylation of KCC2 at Thr906 and Thr1007 is a potent activator of KCC2 activity. Consequently, targeting the WNK-SAPK kinase signaling pathway through small molecular interventions emerges as a promising novel therapeutic strategy for epilepsy.