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이재광,한영은,Oleg Favorov,Mark Tommerdahl,Barry Whitsel,이창준 한국뇌신경과학회 2016 Experimental Neurobiology Vol.25 No.2
Regulation of cell volume is an important aspect of cellular homeostasis during neural activity. This volume regulation is thought to be mediated by activation of specific transporters, aquaporin, and volume regulated anion channels (VRAC). In cultured astrocytes, it was reported that swelling-induced mitogen-activated protein (MAP) kinase activation is required to open VRAC, which are thought to be important in regulatory volume decrease and in the response of CNS to trauma and excitotoxicity. It has been also described that sodium fluoride (NaF), a recognized G-protein activator and protein phosphatase inhibitor, leads to a significant MAP kinase activation in endothelial cells. However, NaF’s effect in volume regulation in the brain is not known yet. Here, we investigated the mechanism of NaF-induced volume change in rat and mouse hippocampal slices using intrinsic optical signal (IOS) recording, in which we measured relative changes in intracellular and extracellular volume as changes in light transmittance through brain slices. We found that NaF (1~5 mM) application induced a reduction in light transmittance (decreased volume) in CA1 hippocampus, which was completely reversed by MAP kinase inhibitor U0126 (10 μM). We also observed that NaF-induced volume reduction was blocked by anion channel blockers, suggesting that NaF-induced volume reduction could be mediated by VRAC. Overall, our results propose a novel molecular mechanism of NaF-induced volume reduction via MAP kinase signaling pathway by activation of VRAC.
Lee, Jaekwang,Favorov, Oleg V,Tommerdahl, Mark,Lee, C. Justin,Whitsel, Barry L. The Korean Society for Brain and Neural Science 2014 Experimental Neurobiology Vol.23 No.1
<P>It has been reported that long-term enhancement of superficial dorsal horn (DH<SUB>s</SUB>) excitatory synaptic transmission underlies central sensitization, secondary hyperalgesia, and persistent pain. We tested whether impaired clearance of K<SUP>+</SUP> and glutamate by glia in DH<SUB>s</SUB> may contribute to initiation and maintenance of the CNS pain circuit and sensorimotor abnormalities. Transient exposure of the spinal cord slice to fluorocitrate (FC) is shown to be accompanied by a protracted <I>decrease</I> of the DH<SUB>s</SUB> optical response to repetitive electrical stimulation of the ipsilateral dorsal root, and by a similarly protracted <I>increase</I> in the postsynaptic response of the DH<SUB>s</SUB> like LTP. It also is shown that LTP<SUB>FC</SUB><I>does not</I> occur in the presence of APV, and becomes progressively <I>smaller</I> as [K<SUP>+</SUP>]<SUB>o</SUB> in the perfusion solution decreased from 3.0 mM to 0.0 mM. Interestingly LTP<SUB>FC</SUB> is <I>reduced</I> by bath application of Bic. Whole-cell patch recordings were carried out to evaluate the effects of FC on the response of DH<SUB>s</SUB> neurons to puffer-applied GABA. The observations reveal that transient exposure to FC is reliably accompanied by a prolonged (>1 hr) depolarizing shift of the equilibrium potential for the DH<SUB>s</SUB> neuron transmembrane ionic currents evoked by GABA. Considered collectively, the findings demonstrate that LTP<SUB>FC</SUB> involves (1) elevation of [K<SUP>+</SUP>]<SUB>o</SUB> in the DH<SUB>s</SUB>, (2) NMDAR activation, and (3) conversion of the effect of GABA on DH<SUB>s</SUB> neurons from inhibition to excitation. It is proposed that a transient impairment of astrocyte energy production can trigger the cascade of dorsal horn mechanisms that underlies hyperalgesia and persistent pain.</P>