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

Abstract

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.

Imaging and serum biomarkers reflecting the functional efficacy of extended erythropoietin treatment in rats following infantile traumatic brain injury

“…In fact, KCC2 influences multiple components of neuronal activity including neuronal survival, inhibitory tone, synaptogenesis, and seizure threshold. 9,32,68,76,92,99 Loss of KCC2 expression occurs with epilepsy, 31 gliomas, 15,65 trauma, 11,12,67 and perinatal brain injury. 37,36,79 Developmentally regulated molecules essential for cerebral function are vulnerable to calpain including KCC2, 37,39,72,108 myelin basic protein, and phosphorylated neurofilament.…”

Cation-chloride cotransporters in neuronal development, plasticity and disease

“…The downregulation of KCC2 is part of a spectrum of changes associated with cellular de-differentiation following neuronal trauma 15,176 . In parallel with, or as a result of, changes in its serine 940 phosphorylation status 32,141 , KCC2 is cleaved at its C-terminal domain by the Ca 2+ - and brain-derived neurotrophic factor (BDNF)-activated protease calpain, leading to a loss of a ~20–40 kDa fragment 23,150,151,286 (FIG. 1d) and reduction of both total and surface-expressed KCC2 protein.…”

“…1d), and it is thus not surprising that calpain-mediated cleavage of KCC2 compromises neuronal Cl − extrusion capacity 150,151 . Furthermore, both serine 940 dephosphorylation and calpain activation have been suggested to regulate the lateral mobility of KCC2 within the plasma membrane, with potential consequences for the synaptic localization of AMPA receptors 29,32,151 . As the C-terminal domain of KCC2 is also important for its ion- transport-independent functions 30 (including formation of the mature spine phenotype 28,29 ), calpain cleavage of KCC2 is likely to contribute to the changes in dendritic spines associated with calpain activation (REFS 32,287,288).…”

“…The molecular cascades that underlie the developmental upregulation of KCC2 in spines remain poorly understood 6,32,44,216 . Embryonic overexpression of BDNF results in precocious upregulation of KCC2 and in an increased number of GABAergic and non-GABAergic synapses 85 .…”

“…Based on their developmental, cellular and subcellular patterns of functional expression, CCCs have turned out to be highly versatile factors in the control of GABAergic and glycinergic signalling. The importance of CCCs in brain function is underscored by the recent discovery of an ion-transport-independent structural role for KCC2 in the morphological and functional maturation of cortical dendritic spines 28–32 . Thus, KCC2 is in a key position to control and coordinate the development of both GABAergic and glutamatergic transmission.…”