RT Journal Article
SR Electronic
T1 Activity-Dependent Cleavage of the K-Cl Cotransporter KCC2 Mediated by Calcium-Activated Protease Calpain
JF The Journal of Neuroscience
JO J. Neurosci.
FD Society for Neuroscience
SP 11356
OP 11364
DO 10.1523/JNEUROSCI.6265-11.2012
VO 32
IS 33
A1 Martin Puskarjov
A1 Faraz Ahmad
A1 Kai Kaila
A1 Peter Blaesse
YR 2012
UL http://www.jneurosci.org/content/32/33/11356.abstract
AB The K-Cl cotransporter KCC2 plays a crucial role in neuronal chloride regulation. In mature central neurons, KCC2 is responsible for the low intracellular Cl− concentration ([Cl−]i) that forms the basis for hyperpolarizing GABAA receptor-mediated responses. Fast changes in KCC2 function and expression have been observed under various physiological and pathophysiological conditions. Here, we show that the application of protein synthesis inhibitors cycloheximide and emetine to acute rat hippocampal slices have no effect on total KCC2 protein level and K-Cl cotransporter function. Furthermore, blocking constitutive lysosomal degradation with leupeptin did not induce significant changes in KCC2 protein levels. These findings indicate a low basal turnover rate of the total KCC2 protein pool. In the presence of the glutamate receptor agonist NMDA, the total KCC2 protein level decreased to about 30% within 4 h, and this effect was blocked by calpeptin and MDL-28170, inhibitors of the calcium-activated protease calpain. Interictal-like activity induced by incubation of hippocampal slices in an Mg2+-free solution led to a fast reduction in KCC2-mediated Cl− transport efficacy in CA1 pyramidal neurons, which was paralleled by a decrease in both total and plasmalemmal KCC2 protein. These effects were blocked by the calpain inhibitor MDL-28170. Taken together, these findings show that calpain activation leads to cleavage of KCC2, thereby modulating GABAergic signaling.