Quest for pharmacological regulators of KCC2

Abstract The K-Cl co-transporter KCC2 play a key role in the control of intracellular chloride homeostasis, which represents a fundamental process regulating many aspects of neuronal functions. The developmentally regulated increase of KCC2 expression and activity during neuronal development is critical for the switch of GABA's action from depolarizing to hyperpolarizing, a process altered in many neurodevelopmental disorders. Moreover, during mature stages, KCC2 activity may undergo a quick downregulation upon stressful events including spinal injury, anoxia or elevated neuronal activity, re-converting GABA signaling to excitatory and contributing to pain, paralysis or seizures. Given the pivotal role played by KCC2 in these processes, the development of selective pharmacological tools able to effectively modulate its activity represents an emerging and promising interventional strategy for the treatment and management of many neurological conditions. In this review we outline the pharmacological toolkit targeting KCC2 and highlight the rationale, expectations and obstacles of developing new means of successfully modulating KCC2.