Modulation of neuronal activity by phosphorylation of the K–Cl cotransporter KCC2

Abstract

The K–Cl cotransporter KCC2 establishes the low intraneuronal Cl− levels required for the hyperpolarizing inhibitory postsynaptic potentials mediated by ionotropic g-aminobutyric acid receptors (GABAARs) and glycine receptors (GlyRs). Decreased KCC2-mediated Cl− extrusion and impaired hyperpolarizing GABAAR- and/or GlyR-mediated currents have been implicated in epilepsy, neuropathic pain, and spasticity. Recent evidence suggests that the intrinsic ion transport rate, cell surface stability, and plasmalemmal trafficking of KCC2 are rapidly and reversibly modulated by the (de)phosphorylation of critical serine, threonine, and tyrosine residues in the C terminus of this protein. Alterations in KCC2 phosphorylation have been associated with impaired KCC2 function in several neurological diseases. Targeting KCC2 phosphorylation directly or indirectly via upstream regulatory kinases might be a novel strategy to modulate GABA- and/or glycinergic signaling for therapeutic benefit.

A Novel Regulatory Locus of Phosphorylation in the C Terminus of the Potassium Chloride Cotransporter KCC2 That Interferes with N-Ethylmaleimide or Staurosporine-mediated Activation*♦

“…This is in line with the observation of phosphorylated Ser 937 and likely Thr 934 in adult brain tissue (57). So far, phosphorylation mainly affected trafficking or the half-lives of KCC2 (5,36). In contrast to these findings, the increased activity of KCC2 T934D or KCC2 S937D was not paralleled by an increase in total amount or cell surface expression of the transporter (Figs.…”

“…The kinase inhibitors lavendustin A, genistein (32), or staurosporine (33) altered KCC2 transport activity in cultured hippocampal neurons, and calyculin (34) and okadaic acid (35), two potent phosphatase inhibitors, blocked activation of KCCs by cell swelling. The important role of phosphorylation was corroborated by the regulatory role of several identified phosphorylation sites in KCC2 (36). Phosphorylation of human threonines Thr 906 and Thr 1007 reduced the intrinsic transport activity of KCC2 (37,38).…”

“…In contrast, phosphorylated Ser 940 increased surface expression and KCC2 transport function (39) as well as membrane clustering (40). Finally, the phosphorylation status of Tyr 903 and Tyr 1087 also regulates KCC2 activity, although the functional consequences of phosphorylation appear to be context-dependent and require further investigation (5,23,36,41,42).…”

Simultaneous two-photon imaging of intracellular chloride concentration and pH in mouse pyramidal neurons in vivo

“…The "ionic plasticity" of GABAergic signaling involves not only the passive flux of Cl − ions through membrane channels but also, a number of ion transporters that regulate [Cl − ] i . Furthermore, this mechanism is under the control of intracellular signaling cascades that regulate the expression patterns as well as functional properties of ion transporters and channels (5,6). With regard to long-term ionic modulation of GABAergic transmission, a case in point is the decrease in [Cl − ] i that is generally thought to take place during maturation of most central neurons.…”

Glycine is able to induce both a motility speed in- and decrease during zebrafish neuronal migration

“…Gain-of-function mutations, however, appear to promote the activity of NKCC1 over KCC2 at this older developmental stage (Figure 3(d)), as indicated by the inhibitor data. Although the molecular details of such a connection between glycine receptor strength and altered functionality of NKCC1/KCC2 remain to be characterized, it has been reported that glycine receptor activity and solute carrier function correlate in late differentiating neurons [24], and a shift in solute carrier expression and activity patterns upon brain lesions or neuropathy has also been reported [25–29]. …”