system would allow for neuronal networks to return to higher levels of plasticity in order to rewire surviving neurons to compensate for damage in the network. In addition, reduced glutamatergic transmission upon KCC2 downregulation may serve as a homeostatic process to compensate for the reduced GABA transmission due to altered chloride extrusion. Oncogenesis Mutations in SLC12A5 are associated with colon cancer. Regulation Transcriptional regulation: TrkB receptor signalling KCC2 is transcriptionally downregulated following central nervous system injury by the TrkB receptor signalling transduction cascade (activated by BDNF and NT-4/5). Post-translational regulation: phosphorylation It is conventionally thought that phosphorylation inactivates or downregulates KCC2, however there is recent evidence to suggest that phosphorylation at different sites on the KCC2 protein determines different regulational outcomes: Wnk1/Wnk3 and tyrosine kinase (i.e. TrkB) phosphorylation downregulates KCC2 activity. PKC phosphorylation of the C-terminus Ser940 residue of the KCC2 protein upregulates KCC2 activity by increasing surface stability. Conversely, Ser940 dephosphorylation leads to enhanced membrane diffusion and endocytosis of KCC2. KCC2 has an extremely high rate of turnover at the plasmalemma (minutes), suggesting that phosphorylation serves as the primary mechanism for rapid regulation. Activity-dependent downregulation KCC2 is downregulated by excitatory glutamate activity on NMDA receptor activity and Ca2+ influx. This process involves rapid dephosphorylation on Ser940 and calpain protease cleavage of KCC2, leading to enhanced membrane diffusion and endocytosis of the transporter, as demonstrated in experiments using single particle tracking. Glutamate release occurs not only at excitatory synapses, but is also known to occur after neuronal damage or ischemic insult. Thus, activity-dependent downregulation may be the underlying mechanism by which KCC2 downregulation occurs following central nervous system injury. See also Solute carrier family References Further reading External links How Brain Injury Leads To Seizures, Memory Problems - medical news, 20 Oct 2006. Solute carrier family