RT Journal Article
SR Electronic
T1 Early Changes in KCC2 Phosphorylation in Response to Neuronal Stress Result in Functional Downregulation
JF The Journal of Neuroscience
JO J. Neurosci.
FD Society for Neuroscience
SP 1642
OP 1650
DO 10.1523/JNEUROSCI.3104-06.2007
VO 27
IS 7
A1 Hiroaki Wake
A1 Miho Watanabe
A1 Andrew J. Moorhouse
A1 Takashi Kanematsu
A1 Shoko Horibe
A1 Noriyuki Matsukawa
A1 Kiyofumi Asai
A1 Kosei Ojika
A1 Masato Hirata
A1 Junichi Nabekura
YR 2007
UL http://www.jneurosci.org/content/27/7/1642.abstract
AB The K+ Cl− cotransporter KCC2 plays an important role in chloride homeostasis and in neuronal responses mediated by ionotropic GABA and glycine receptors. The expression levels of KCC2 in neurons determine whether neurotransmitter responses are inhibitory or excitatory. KCC2 expression is decreased in developing neurons, as well as in response to various models of neuronal injury and epilepsy. We investigated whether there is also direct modulation of KCC2 activity by changes in phosphorylation during such neuronal stressors. We examined tyrosine phosphorylation of KCC2 in rat hippocampal neurons under different conditions of in vitro neuronal stress and the functional consequences of changes in tyrosine phosphorylation. Oxidative stress (H2O2) and the induction of seizure activity (BDNF) and hyperexcitability (0 Mg2+) resulted in a rapid dephosphorylation of KCC2 that preceded the decreases in KCC2 protein or mRNA expression. Dephosphorylation of KCC2 is correlated with a reduction of transport activity and a decrease in [Cl−]i, as well as a reduction in KCC2 surface expression. Manipulation of KCC2 tyrosine phosphorylation resulted in altered neuronal viability in response to in vitro oxidative stress. During continued neuronal stress, a second phase of functional KCC2 downregulation occurs that corresponds to decreases in KCC2 protein expression levels. We propose that neuronal stress induces a rapid loss of tyrosine phosphorylation of KCC2 that results in translocation of the protein and functional loss of transport activity. Additional understanding of the mechanisms involved may provide means for manipulating the extent of irreversible injury resulting from different neuronal stressors.