Biomolecules & Therapeutics

The Korean Society of Applied Pharmacology (한국응용약물학회)
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Sustained Intracellular Acidosis Triggers the Na+/H+ Exchager-1 Activation in Glutamate Excitotoxicity

  • Received : 2017.02.02
  • Accepted : 2017.03.18
  • Published : 2017.11.01
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Abstract

The $Na^+/H^+$ exchanger-1 (NHE-1) is a ubiquitously expressed pH-regulatory membrane protein that functions in the brain, heart, and other organs. It is increased by intracellular acidosis through the interaction of intracellular $H^+$ with an allosteric modifier site in the transport domain. In the previous study, we reported that glutamate-induced NHE-1 phosphorylation mediated by activation of protein kinase C-${\beta}$ (PKC-${\beta}$) in cultured neuron cells via extracellular signal-regulated kinases (ERK)/p90 ribosomal s6 kinases (p90RSK) pathway results in NHE-1 activation. However, whether glutamate stimulates NHE-1 activity solely by the allosteric mechanism remains elusive. Cultured primary cortical neuronal cells were subjected to intracellular acidosis by exposure to $100{\mu}M$ glutamate or 20 mM $NH_4Cl$. After the desired duration of intracellular acidosis, the phosphorylation and activation of PKC-${\beta}$, ERK1/2 and p90RSK were determined by Western blotting. We investigated whether the duration of intracellular acidosis is controlled by glutamate exposure time. The NHE-1 activation increased while intracellular acidosis sustained for >3 min. To determine if sustained intracellular acidosis induced NHE-1 phosphorylation, we examined phosphorylation of NHE-1 induced by intracellular acidosis by transient exposure to $NH_4Cl$. Sustained intracellular acidosis led to activation and phosphorylation of NHE-1. In addition, sustained intracellular acidosis also activated the PKC-${\beta}$, ERK1/2, and p90RSK in neuronal cells. We conclude that glutamate stimulates NHE-1 activity through sustained intracellular acidosis, which mediates NHE-1 phosphorylation regulated by PKC-${\beta}$/ERK1/2/p90RSK pathway in neuronal cells.

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References

  1. Chesler, M. and Kaila K. (1992) Modulation of pH by neuronal activity. Trends Neurosci. 15, 396-402. https://doi.org/10.1016/0166-2236(92)90191-A
  2. DeVries, S. H. (2001) Exocytosed protons feedback to suppress the $Ca^{2+}$ current in mammalian cone photoreceptors. Neuron 32, 1107-1117. https://doi.org/10.1016/S0896-6273(01)00535-9
  3. Dixon, D. B., Takahashi, K. I. and Copenhagen, D. R. (1993) L-glutamate suppresses HVA calcium current in catfish horizontal cells by raising intracellular proton concentration. Neuron 11, 267-277. https://doi.org/10.1016/0896-6273(93)90183-R
  4. Hartley, Z. and Dubinsky, J. M. (1993) Changes in intracellular pH associated with glutamate excitotoxicity. J. Neurosci. 13, 4690-4699. https://doi.org/10.1523/JNEUROSCI.13-11-04690.1993
  5. Haworth, R. S., McCann, C., Snabaitis, A. K., Roberts, N. A. and Avkiran, M. (2003) Stimulation of the plasma membrane $Na^+/H^+$ exchanger NHE1 by sustained intracellular acidosis. Evidence for a novel mechanism mediated by the ERK pathway. J. Biol. Chem. 278, 31676-31684. https://doi.org/10.1074/jbc.M304400200
  6. Haworth, R. S., Dashnyam, S. and Avkiran, M. (2006) Ras triggers acidosis-induced activation of the extracellular-signal-regulated kinase pathway in cardiac myocytes. Biochem. J. 399, 493-501. https://doi.org/10.1042/BJ20051628
  7. Irwin, R. P., Lin, S. Z., Long, R. T. and Paul, S. M. (1994) N-methyl-D-aspartate induces a rapid, reversible, and calcium-dependent intracellular acidosis in cultured rat hippocampal neurons. J. Neurosci. 14, 1352-1357. https://doi.org/10.1523/JNEUROSCI.14-03-01352.1994
  8. Itoh, S., Ding, B., Bains, C. P., Wang, N., Takeishi, Y., Jalili, T., King, G. L., Walsh, R. A., Yan, C. and Abe, J. (2005) Role of p90 ribosomal S6 kinase (p90RSK) in reactive oxygen species and protein kinase $C{\beta}$ (PKC-TEX>${\beta}$)-mediated cardiac troponin I phosphorylation. J. Biol. Chem. 280, 24135-24142. https://doi.org/10.1074/jbc.M413015200
  9. Jinadasa, T., Szabo, E. Z., Numat, M. and Orlowski, J. (2014) Activation of AMP-activated protein kinase regulates hippocampal neuronal pH by recruiting $Na^+/H^+$ exchanger NHE5 to the cell surface. J. Biol. Chem. 289, 20879-20897. https://doi.org/10.1074/jbc.M114.555284
  10. Jung, Y. S., Ryu, B. R., Lee, B. K., Mook-Jung, I., Kim, S. U., Lee, S. H., Baik, E. J. and Moon, C. H. (2004) Role for PKC-epsilon in neuronal death induced by oxidative stress. Biochem. Biophys. Res. Comm. 320, 789-794. https://doi.org/10.1016/j.bbrc.2004.05.217
  11. Kersh, A. E., Hartzler, L. K., Havlin, K., Hubbell, B. B., Nanagas, V., Kalra, A., Chua, J., Whitesell, R., Ritucci, N. A., Dean, J. B. and Putnam, R. W. (2009) pH regulating transporters in neurons from various chemosensitive brainstem regions in neonatal rats. Am. J. Physiol. Regul. Integr. Comp. Physiol. 297, R1409-R1420. https://doi.org/10.1152/ajpregu.91038.2008
  12. Kim, J., Jung, Y. S., Han, W., Kim, M. Y., Namkung, W., Lee, B. H., Yi, K. Y., Yoo, S. E., Lee, M. G. and Kim, K. H. (2007) Pharmacodynamic characteristics and cardioprotective effects of new NHE1 inhibitors. Eur. J. Pharmacol. 567, 131-138. https://doi.org/10.1016/j.ejphar.2007.03.056
  13. Lee, B. K., Lee, D. H., Park, S., Park, S. L., Yoon, J. S., Lee, M. G., Lee, S., Yi, K. Y., Yoo, S. E., Lee, K. H., Kim, Y. S., Lee, S. H., Baik, E. J., Moon, C. H. and Jung, Y. S. (2009) Effects of KR-33028, a novel $Na^+/H^+$ exchanger-1 inhibitor, on glutamate-induced neuronal cell death and ischemia-induced cerebral infarct. Brain Res. 1248, 22-30. https://doi.org/10.1016/j.brainres.2008.10.061
  14. Lee, B. K. and Jung, Y. S. (2012) The $Na^+/H^+$ exchanger-1 inhibitor cariporide prevents glutamate-induced necrotic neuronal death by inhibiting mitochondrial $Ca^{2+}$ overload. J. Neurosci. Res. 90, 860-869. https://doi.org/10.1002/jnr.22818
  15. Lee, B. K., Yoon, J. S., Lee, M. G. and Jung, Y. S. (2014) Protein kinase C-${\beta}$ mediates neuronal activation of $Na^+/H^+$ exchanger-1 during glutamate excitotoxicity. Cell. Signal. 26, 697-704. https://doi.org/10.1016/j.cellsig.2013.12.011
  16. Lipp, P. and Reither, G. (2011) Protein kinase C: The "Masters" of calcium and lipid. Cold Spring Harb. Perspect. Biol. 3, a004556.
  17. Matsumoto, Y., Yamamoto, S., Suzuki, Y., Tsuboi, T., Terakawa, S., Ohashi, N. and Umemura, K. (2004) $Na^+/H^+$ exchanger inhibitor, SM-20220, is protective against excitotoxicity in cultured cortical neurons. Stroke 35, 185-190.
  18. Rathje, M., Fang, H., Bachman, J. L., Anggono, V., Gether, U., Huganir, R. L. and Madsen, K. L. (2013) AMPA receptor pHluorin-GluA2 reports NMDA receptor-induced intracellular acidification in hippocampal neurons. Proc. Natl. Acad. Sci. U.S.A. 110, 14426-14431. https://doi.org/10.1073/pnas.1312982110
  19. Rocha, M. A., Crockett, D. P., Wong, L. Y., Richardson, J. R. and Sonsalla, P. K. (2008) $Na^+/H^+$exchanger inhibition modifies dopamine neurotransmission during normal and metabolic stress conditions. J. Neurochem. 106, 231-243. https://doi.org/10.1111/j.1471-4159.2008.05355.x
  20. Roos, A. and Boron, W. F. (1981) Intracellular pH. Physiol. Rev. 61, 296-434. https://doi.org/10.1152/physrev.1981.61.2.296
  21. Ruffin, V. A., Salameh, A. I., Boron, W. F. and Parker, M. D. (2014) Intracellular pH regulation by acid-base transporters in mammalian neurons. Front. Physiol. 5, 43.
  22. Snabaitis, A. K., Cuello, F. and Avkiran, M. (2008) Protein kinase B/Akt phosphorylates and inhibits the cardiac $Na^+/H^+$ exchanger NHE1. Circ. Res. 103, 881-890. https://doi.org/10.1161/CIRCRESAHA.108.175877
  23. Takahashi, E., Abe, J., Gallis, B., Aebersold, R., Spring, D. J., Krebs, E. G. and Berk, B. C. (1999) p90(RSK) is a serum-stimulated $Na^+/H^+$ exchanger isoform-1 kinase. Regulatory phosphorylation of serine 703 of $Na^+/H^+$ exchanger isoform-1. J. Biol. Chem. 274, 20206-20214. https://doi.org/10.1074/jbc.274.29.20206
  24. Tang, C. M., Dichter, M. and Morad, M. (1990) Modulation of the N-methyl-D-aspartate channel by extracellular $H^+$. Proc. Natl. Acad. Sci. U.S.A. 87, 6445-6449. https://doi.org/10.1073/pnas.87.16.6445
  25. Thomas, R. C. (1989) Proton channels in snail neurons. Does calcium entry mimic the effects of proton influx? Ann. N. Y. Acad. Sci. 574, 287-293. https://doi.org/10.1111/j.1749-6632.1989.tb25165.x
  26. Wang, G. J., Randall, R. D. and Thayer, S. A. (1994) Glutamate-induced intracellular acidification of cultured hippocampal neurons demonstrates altered energy metabolism resulting from $Ca^{2+}$ loads. J. Neurophysiol. 72, 2563-2569. https://doi.org/10.1152/jn.1994.72.6.2563
  27. Yamamoto, T., Swietach, P., Rossini, A., Loh, S. H., Vaughan-Jones, R. D. and Spitzer, K. W. (2005) Functional diversity of electrogenic $Na^+-HCO_3{^-}$ cotransport in ventricular myocytes from rat, rabbit and guinea pig. J. Physiol. 562, 455-475. https://doi.org/10.1113/jphysiol.2004.071068

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