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The Journal of Neuroscience, February 14, 2007, 27(7):1642-1650; doi:10.1523/JNEUROSCI.3104-06.2007

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Cellular/Molecular
Early Changes in KCC2 Phosphorylation in Response to Neuronal Stress Result in Functional Downregulation

Hiroaki Wake,^1,2 Miho Watanabe,¹ Andrew J. Moorhouse,³ Takashi Kanematsu,⁴ Shoko Horibe,^1,6 Noriyuki Matsukawa,² Kiyofumi Asai,⁵ Kosei Ojika,² Masato Hirata,⁴ and Junichi Nabekura^1,6,7

¹Division of Homeostatic Development, National Institute of Physiological Sciences, Okazaki 444-8585, Japan, ²Department of Neurology and Neuroscience, Nagoya City University Graduate School of Medical Sciences, Mizuho-ku, Nagoya 467-8601, Japan, ³Department of Physiology and Pharmacology, School of Medical Sciences, University of New South Wales, Sydney, New South Wales 2052, Australia, ⁴Molecular and Cellular Biochemistry, Faculty of Dental Science, Kyushu University, Fukuoka 812-8582, Japan, ⁵Department of Molecular Neurobiology, Nagoya City University Graduate School of Medical Sciences, Nagoya 467-8601, Japan, ⁶School of Life Science, The Graduate University for Advanced Studies, Hayama 240-0193, Japan, and ⁷Core Research for the Evolutionary Science and Technology, Japan Science and Technology Corporation, Saitama 332-0012, Japan

Correspondence should be addressed to Dr. Junichi Nabekura, Division of Homeostatic Development, Department of Developmental Physiology, National Institute of Physiological Sciences, Okazaki 44-8585, Japan. Email: nabekura{at}nips.ac.jp

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.

Key words: KCC2; neurons; E_Cl^–; Cl^– homeostasis; oxidative stress; cell death

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Received Feb. 27, 2006; revised Jan. 4, 2007; accepted Jan. 5, 2007.

Correspondence should be addressed to Dr. Junichi Nabekura, Division of Homeostatic Development, Department of Developmental Physiology, National Institute of Physiological Sciences, Okazaki 44-8585, Japan. Email: nabekura{at}nips.ac.jp

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