Crossing the Chloride Channel: The Current and Potential Therapeutic Value of the Neuronal K⁺-Cl^- Cotransporter KCC2

Figure 2

Neuronal Cl⁻ volume is reciprocally regulated via NKCC1 and KCC2. In healthy mature neurons, is low due to the opposing activity profiles of NKCC1 and KCC2. This promotes R-mediated hyperpolarization, which is critical for the proper balance of excitation-inhibition in neuronal circuits (left panel). In neurons implicated in multiple neuropsychiatric conditions driven by hyperexcitable circuits (e.g., seizures, neuropathic pain, spasticity, schizophrenia, and others), are elevated due to increased NKCC1 activity, and/or decreased KCC2 activity, promoting R-mediated membrane depolarization and excitation (right panel).