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

Trends Neurosci. 2013 Dec;36(12):726-737. doi: 10.1016/j.tins.2013.08.006. Epub 2013 Oct 15.


The K-Cl cotransporter KCC2 establishes the low intraneuronal Cl- levels required for the hyperpolarizing inhibitory postsynaptic potentials mediated by ionotropic γ-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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • Animals
  • Humans
  • K Cl- Cotransporters
  • Models, Biological
  • Nervous System Diseases / metabolism
  • Nervous System Diseases / pathology
  • Neurons / metabolism*
  • Phosphorylation
  • Receptors, GABA
  • Receptors, Glycine
  • Signal Transduction / physiology
  • Symporters / metabolism*


  • Receptors, GABA
  • Receptors, Glycine
  • Symporters