K-Cl cotransporter KCC2--a moonlighting protein in excitatory and inhibitory synapse development and function.

The K-Cl cotransporter KCC2 has two entirely independent biological actions as either an ion transporter or a structural protein orchestrating the organization of the cytoskeleton in neuronal structures. The K-Cl cotransport by KCC2 is central for hyperpolarizing inhibitory signaling, which is based on chloride currents mediated by γ-aminobutyric acid (GABA)- or glycine-gated receptor channels. In contrast, the structural role of KCC2 seems to be crucially involved in the maturation and regulation of excitatory glutamatergic synapses. This dual role at GABAergic/glycinergic and glutamatergic synapses makes KCC2 a key molecule in the regulation of inhibitory and excitatory signaling. Therefore, KCC2 is most likely involved in the synchronization of the two types of activity during network formation in the immature system and a similar synchronizing role might also be important under physiological and pathological conditions in mature neuronal networks. In this review, we explore new findings on the regulation of KCC2 by protease-mediated cleavage and on the structural role of KCC2 in spine morphogenesis and glutamate receptor clustering. We then discuss the implications of the putative interaction between the independent functions of the transporter and overlapping regulatory mechanisms in a neurophysiological context. In addition, we look at the multifunctional properties of KCC2 in the light of evolution and propose that KCC2 belongs to the group of moonlighting (multifunctional) proteins.