ABSTRACT It is known that activated N-methyl-D-aspartate receptors (NMDARs) are a major route of ex-cessive calcium ion (Ca2+) entry in central neu-rons, which may activate degradative processes and thereby cause cell death. Therefore, NMD- ARs are now recognized to play a key role in the development of many diseases associated with injuries to the central nervous system (CNS). However, it remains a mystery how NMDAR ac-tivity is recruited in the cellular processes leading to excitotoxicity and how NMDAR activ-ity can be controlled at a physiological level. The sodium ion (Na+) is the major cation in ex-tracellular space. With its entry into the cell, Na+ can act as a critical intracellular second mes-senger that regulates many cellular functions. Recent data have shown that intracellular Na+ can be an important signaling factor underlying the up-regulation of NMDARs. While Ca2+ influx during the activation of NMDARs down-regu-lates NMDAR activity, Na+ influx provides an essential positive feedback mechanism to over- come Ca2+-induced inhibition and thereby po-tentiate both NMDAR activity and inward Ca2+ flow. Extensive investigations have been con-ducted to clarify mechanisms underlying Ca2+- mediated signaling. This review focuses on the roles of Na+ in the regulation of Ca2+-mediated NMDAR signaling and toxicity.
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nullYu, X. , R. Groveman, B. , Fang, X. and Lin, S. (2010) The role of intracellular sodium (Na+) in the regulation of calcium (Ca2+)-mediated signaling and toxicity. Health, 2, 8-15. doi: 10.4236/health.2010.21002.
 Berridge, M.J., Lipp, P. and Bootman, M.D. (2000) The versatility and universality of calcium signaling. Nat Rev Mol Cell Biol, 1, 11-21.
Clapham, D.E. (1995) Calcium signaling. Cell, 80, 259-268.
Dong, Z., Saikumar, P., Weinberg, J.M. and Venkatacha-lam, M.A. (2006) Calcium in cell injury and death. Ann. Rev Pathol., 1, 405-434.
Choi, D.W. (1995) Calcium: Still center-stage in hy-poxic-ischemic neuronal death. Trends. Neurosci., 18, 58-60.
Forder, J.P. and Tymianski, M. (2009) Postsynaptic mechanisms of excitotoxicity: Involvement of postsy-naptic density proteins, radicals, and oxidant molecules. Neuroscience, 158, 293-300.
Lipton, S.A. (2006) Paradigm shift in neuroprotection by NMDA receptor blockade: Memantine and beyond. Nat. Rev. Drug Discov., 5, 160-170.
Mody, I. and MacDonald, J.F. (1995) NMDA recep-tor-dependent excitotoxicity: The role of intracellular Ca2+ release. Trends. Pharmacol. Sci., 16, 356-359.
Soriano, F.X. and Hardingham, G.E. (2007) Compart-mentalized NMDA receptor signaling to survival and death. J. Physiol., 584, 381-387.
Tymianski, M. and Tator, C.H. (1996) Normal and abnor-mal calcium homeostasis in neurons: A basis for the pathophysiology of traumatic and ischemic central nervous system injury. Neurosurgery, 38, 1176-1195.
Zipfel, G.J., Babcock, D.J., Lee, J.M. and Choi, D.W. (2000) Neuronal apoptosis after CNS injury: The roles of glutamate and calcium. J. Neurotrauma., 17, 857-869.
Bredesen, D.E. (2000) Apoptosis: Overview and signal transduction pathways [In Process Citation]. J. Neuro-trauma, 17, 801-810.
Fiskum, G. (2000) Mitochondrial participation in ischemic and traumatic neural cell death [In Process Ci-tation]. J. Neurotrauma., 17, 843-855.
Krupp, J.J., Vissel, B., Thomas, C.G., Heinemann, S.F. and Westbrook, G.L. (1999) Interactions of calmodulin and alpha-actinin with the NR1 subunit modulate Ca2+- dependent inactivation of NMDA receptors. J. Neurosci., 19, 1165-1178.
Ehlers, M.D., Zhang, S., Bernhardt, J.P. and Huganir, R.L. (1996) Inactivation of NMDA Receptors by direct inter-action of calmodulin with the NR1 subunit. Cell, 84, 745-755.
Wechsler, A. and Teichberg, V.I. (1998) Brain spectrin binding to the NMDA receptor is regulated by phosphory-lation, calcium and calmodulin. EMBO J., 17, 3931-3939.
Zhang, S., Ehlers, M.D., Bernhardt, J.P., Su, C.T. and Huganir, R.L. (1998) Calmodulin mediates calcium de-pendent inactivation of N-methyl-D-aspartate receptors. Neuron, 21, 443-453.
Lieberman, D.N. and Mody, I. (1994) Regulation of NMDA channel function by endogenous Ca2+- dependent phosphatase. Nature, 369, 235-239.
Mulkey, R.M., Endo, S., Shenolikar, S. and Malenka, R.C. (1994) Involvement of a calcineurin/inhibitor-1 phos-phatase cascade in hippocampal long-term depression. Nature, 369, 486-488.
Tong, G., Shepherd, D. and Jahr, C.E. (1995) Synaptic desensitization of NMDA receptors by calcineurin. Sci-ence, 267, 1510-1512.
Dingledine, R., Borges, K., Bowie, D. and Traynelis, S.F. (1999) The glutamate receptor ion channels. Pharmacol. Rev., 51, 7-61.
Kyrozis, A., Albuquerque, C., Gu, J. and MacDermott, A.B. (1996) Ca(2+)-dependent inactivation of NMDA receptors: Fast kinetics and high Ca2+ sensitivity in rat dorsal horn neurons. J. Physiol. (Lond), 495, 449-463.
Mayer, M.L. and Westbrook, G.L. (1987) The physiology of excitatory amino acids in the vertebrate central nervous system. Prog. Neurobiol., 28, 197-276.
McBain, C.J. and Mayer, M.L. (1994) N-Methyl-D-aspar-tic acid receptor structure and function. Physiol. Rev., 74, 723-760.
Nicholls, D. and Attwell, D. (1990) The release and up-take of excitatory amino acids. Trends in Pharmacologi-cal Sciences, 11, 462-468.
Rose, C.R. (2002) Na+ signals at central synapses. Neu-roscientist., 8, 532-539.
Rose, C.R. and Konnerth, A. (2001) NMDA recep-tor-mediated Na+ signals in spines and dendrites. J. Neurosci., 21, 4207-4214.
Yu, X.M. (2006) The role of intracellular sodium (Na+) in the regulation of NMDA receptor-mediated channel ac-tivity and toxicity. Mol Neurobiol., 3, 63-79.
Yu, X.M. and Salter, M.W. (1998) Gain control of NMDA- receptor currents by intracellular sodium. Nature, 396, 469-474.
Yu, X.M. and Salter, M.W. (1999) Src, a molecular switch governing gain control of synaptic transmission mediated by N-methyl-D-aspartate receptors. Proc. Natl. Acad. Sci. USA, 96, 7697-7704.
Xin, W.K. et al. (2005) A functional interaction of sodium and calcium in the regulation of NMDA receptor activity by remote NMDA receptors. J. Neurosci., 25, 139-148.
Ballard-Croft, C., Carlson, D., Maass, D.L. and Horton, J.W. (2004) Burn trauma alters calcium transporter pro-tein expression in the heart. J. Appl. Physiol., 97, 1470-1476.
Banasiak, K.J., Burenkova, O. and Haddad, G.G. (2004) Activation of voltage-sensitive sodium channels during oxygen deprivation leads to apoptotic neuronal death. Neuroscience, 126, 31-44.
Baptiste, D.C. and Fehlings, M.G. (2007) Update on the treatment of spinal cord injury. Prog. Brain Res., 161, 217-233.
Bauer, R., Walter, B., Fritz, H. and Zwiener, U. (1999) Ontogenetic aspects of traumatic brain edema: Facts and suggestions. Exp. Toxicol Pathol., 51, 143-150.
Friedman, J.E. and Haddad, G.G. (1994) Anoxia induces an increase in intracellular sodium in rat central neurons in vitro. Brain Res., 663, 329-334.
Schwartz, G. and Fehlings, M.G. (2002) Secondary injury mechanisms of spinal cord trauma: A novel therapeutic approach for the management of secondary pathophysi-ology with the sodium channel blocker riluzole. Prog. Brain Res., 137, 177-190.
Strichartz, G., Rando, T. and Wang, G.K. (1987) An inte-grated view of the molecular toxinology of sodium channel gating in excitable cells. Ann. Rev. Neurosci., 10, 237-67.
Sheldon, C., Diarra, A., Cheng, Y.M. and Church, J. (2004) Sodium influx pathways during and after anoxia in rat hippocampal neurons. J. Neurosci., 24, 11057-11069.
Choi, D.W. (1993) NMDA receptors and AMPA/kainate receptors mediate parallel injury in cerebral cortical cul-tures subjected to oxygen-glucose deprivation. Prog. Brain Res., 96, 137-43.
Blaustein, M.P., Fontana, G. and Rogowski, R.S. (1996) The Na(+)-Ca2+ exchanger in rat brain synaptosomes: Kinetics and regulation. Ann. N. Y. Acad. Sci., 779, 300-17.
Koch, R.A. and Barish, M.E. (1994) Perturbation of intra-cellular calcium and hydrogen ion regulation in cultured mouse hippocampal neurons by reduction of the sodium ion concentration gradient. J. Neurosci., 14, 2585-2593.
Baxter, K.A. and Church, J. (1996) Characterization of acid extrusion mechanisms in cultured fetal rat hippo-campal neurones. J. Physiol. (Lond), 493, 457-470.
Boonstra, J. et al. (1983) Ionic responses and growth stimulation induced by nerve growth factor and epidermal growth factor in rat pheochromocytoma (PC12) cells. J. Cell Biol., 97, 92-98.
Moolenaar, W.H., Defize, L.H. and de Laat, S.W. (1986) Ionic signaling by growth factor receptors. J. Exp. Biol., 124, 359-73.
Moolenaar, W.H., Tsien, R.Y., van der Saag, P.T. and de Laat, S.W. (1983) Na+/H+ exchange and cytoplasmic pH in the action of growth factors in human fibroblasts. Na-ture, 304, 645-648.
Sin, W.C. et al. (2009) Regulation of early neurite morphogenesis by the Na+/H+ exchanger NHE1. J. Neurosci., 29, 8946-8959.
Bortner, C.D. and Cidlowski, J.A. (2003) Uncoupling cell shrinkage from apoptosis reveals that Na+ influx is re-quired for volume loss during programmed cell death. J. Biol Chem, 278, 39176-39184.
Werling, L.L., Brown, S.R., Puttfarcken, P. and Cox, B.M. (1986) Sodium regulation of agonist binding at opioid re-ceptors. II. Effects of sodium replacement on opioid bind-ing in guinea pig cortical membranes. Mol Pharmacol, 30, 90-95.
Zhang, D. et al. (2009) Na, K-ATPase activity regulates AMPA receptor turnover through proteasome-mediated proteolysis. J. Neurosci., 29, 4498-4511.
Bhattacharjee, A. et al. (2003) Slick (Slo2.1), a rap-idly-gating sodium-activated potassium channel inhibited by ATP. J. Neurosci, 23, 11681-11691.
Bhattacharjee, A. and Kaczmarek, L.K. (2005) For K(+) channels, Na(+) is the new Ca(2+). Trends Neurosci, 28, 422-428.
Dryer, S.E. (2003) Molecular identification of the Na+- activated K+ channel. Neuron, 37, 727-728.
Niu, X.W. and Meech, R.W. (2000) Potassium inhibition of sodium-activated potassium (K(Na)) channels in guinea- pig ventricular myocytes. J. Physiol, 526(Pt 1), 81-90.
Yuan, A. et al. (2003) The sodium-activated potassium channel is encoded by a member of the Slogene family. Neuron, 37, 765-773.
Liu, X. and Stan, L.L. (2004) Sodium-activated potassium conductance participates in the depolarizing afterpotential following a single action potential in rat hippocampal CA1 pyramidal cells. Brain Res., 1023, 185-192.
Agrawal, S.K. and Fehlings, M.G. (1996) Mechanisms of secondary injury to spinal cord axons in vitro: Role of Na+, Na(+)-K(+)-ATPase, the Na(+)-H+exchanger, and the Na(+)-Ca2+ exchanger. J. Neurosci., 16, 545-552.
Agrawal, S.K. and Fehlings, M.G. (1997) The effect of the sodium channel blocker QX-314 on recovery after acute spinal cord injury. J. Neurotrauma., 14, 81-88.
Fehlings, M.G. and Agrawal, S. (1995) Role of sodium in the pathophysiology of secondary spinal cord injury. Spine, 20, 2187-2191.
Hains, B.C., Saab, C.Y., Lo, A.C. and Waxman, S.G. (2004) Sodium channel blockade with phenytoin protects spinal cord axons, enhances axonal conduction, and im-proves functional motor recovery after contusion SCI. Exp. Neurol., 188, 365-377.
Teng, Y.D. and Wrathall, J.R. (1997) Local blockade of sodium channels by tetrodotoxin ameliorates tissue loss and long-term functional deficits resulting from experi-mental spinal cord injury. J. Neurosci., 17, 4359-4366.
Cummins, T.R. and Waxman, S.G. (1997) Downregula-tion of tetrodotoxin-resistant sodium currents and up- regulation of a rapidly repriming tetrodotoxin-sensitive sodium current in small spinal sensory neurons after nerve injury. J. Neurosci., 17, 3503-3514.
Appelgren, L., Janson, M., Nitescu, P. and Curelaru, I. (1996) Continuous intracisternal and high cervical in-trathecal bupivacaine analgesia in refractory head and neck pain [see comments]. Anesthesiology, 84, 256-272.
Cox, J.J. et al. (2006) An SCN9A channelopathy causes congenital inability to experience pain. Nature, 444, 894- 898.
Dib-Hajj, S., Black, J.A., Cummins, T.R. and Waxman, S.G. (2002) NaN/Nav1.9: A sodium channel with unique properties. Trends Neurosci., 25, 253-259.
Waxman, S.G. and Hains, B.C. (2006) Fire and phantoms after spinal cord injury: Na+ channels and central pain. Trends Neurosci., 29, 207-215.
Rogawski, M.A. and Loscher, W. (2004) The neurobiology of antiepileptic drugs. Nat. Rev. Neurosci., 5, 553-564.
Mentzer, R.M., Lasley, R.D., Jessel, A. and Karmazyn, M. (2003) Intracellular sodium hydrogen exchange inhibition and clinical myocardial protection. Ann. Thorac. Surg., 75, S700-S708.
Vornov, J.J., Thomas, A.G. and Jo, D. (1996) Protective effects of extracellular acidosis and blockade of so-dium/hydrogen ion exchange during recovery from metabolic inhibition in neuronal tissue culture. J. Neuro-chem., 67, 2379-2389.
Kohr, G., De Koninck, Y. and Mody, I. (1993) Properties of NMDA receptor channels in neurons acutely isolated from epileptic (kindled) rats. J. Neurosci., 13, 3612-3627.
Yu, X.M., Askalan, R., Keil, G.J.I. and Salter, M.W. (1997) NMDA channel regulation by channel-associated protein tyrosine kinase src. Science, 275, 674-678.
Baker, A.J., Moulton, R.J., MacMillan, V.H. and Shedden, P. M. (1993) Excitatory amino acids in cerebrospinal fluid following traumatic brain injury in humans. J. Neurosurg., 79, 369-372.
Persson, L. and Hillered, L. (1992) Chemical monitoring of neurosurgical intensive care patients using intracerebral microdialysis. J. Neurosurg., 76, 72-80.
Benveniste, H., Drejer, J., Schousboe, A. and Diemer, N.H. (1984) Elevation of the extracellular concentrations of glutamate and aspartate in rat hippocampus during transient cerebral ischemia monitored by intracerebral microdialysis. J. Neurochem., 43, 1369-1374.
Chen, H.-S.V. and Lipton, S.A. (2005) Pharmacological implications of two distinct mechanisms of interaction of memantine with NMDA-gated channels. J. Pharmacol. Exp. Ther., 314, 961-971.
Lipton, S.A. (2004) Paradigm shifts in NMDA receptor antagonist drug development: Molecular mechanism of uncompetitive inhibition by memantine in the treatment of Alzheimer’s disease and other neurologic disorders. J. Alzheimers. Dis., 6, S61-S74.
Lipton, P. (1999) Ischemic cell death in brain neurons. Physiol Rev., 79, 1431-1568.
Xin, W.K. et al. (2005) The removal of extracellular calcium: A novel mechanism underlying the recruitment of N-methyl-d-aspartate (NMDA) receptors in neurotox-icity. Eur. J. Neurosci., 21, 622-636.
Giardina, S.F. and Beart, P.M. (2002) Kainate receptor- mediated apoptosis in primary cultures of cerebellar gran-ule cells is attenuated by mitogen-activated protein and cyclin-dependent kinase inhibitors. Br. J. Pharmacol., 135, 1733-1742.
Ohyashiki, T., Satoh, E., Okada, M., Takadera, T. and Sa-hara, M. (2002) Nerve growth factor protects against alu-minum-mediated cell death. Toxicology, 176, 195-207.
Sawyer, T.W. (1995) Practical applications of neuronal tissue culture in in vitro toxicology. Clin. Exp. Pharmacol. Physiol., 22, 295-296.
Wang, X., Mori, T., Sumii, T. and Lo, E.H. (2002) He-moglobin-induced cytotoxicity in rat cerebral cortical neurons: Caspase activation and oxidative stress. Stroke, 33, 1882-1888.
Westbrook, G.L., Krupp, J.J. and Vissel, B. (1997) Cy-toskeletal interactions with glutamate receptors at central synapses. Soc. Gen. Physiol Ser., 52, 163-175.
Hardingham, N.R. et al. (2006) Extracellular calcium regulates postsynaptic efficacy through group 1 me-tabotropic glutamate receptors. J. Neurosci., 26, 6337-6345.
Rusakov, D.A. and Fine, A. (2003) Extracellular Ca2+ depletion contributes to fast activity-dependent modulation of synaptic transmission in the brain. Neuron, 37, 287-297.
Vassilev, P.M., Mitchel, J., Vassilev, M., Kanazirska, M. and Brown, E.M. (1997) Assessment of frequency-dependent alterations in the level of extracellular Ca2+ in the synaptic cleft. Biophys. J., 72, 2103-2116.
Heinemann, U. and Hamon, B. (1986) Calcium and epi-leptogenesis. Exp. Brain Res., 65, 1-10.
Ekholm, A., Kristian, T. and Siesjo, B.K. (1995) Influence of hyperglycemia and of hypercapnia on cellular calcium transients during reversible brain ischemia. Exp. Brain Res., 104, 462-466.
Harris, R.J., Symon, L., Branston, N.M. and Bayhan, M. (1981) Changes in extracellular calcium activity in cere-bral ischaemia. J. Cereb. Blood Flow Metab., 1, 203-209.
Nicholson, C., Bruggencate, G.T., Steinberg, R. and Stockle, H. (1977) Calcium modulation in brain extracellular mi-croenvironment demonstrated with ion-selective micropi-pette. Proc. Natl. Acad. Sci. USA, 74, 1287-1290.
Smith, M.T., Thor, H. and Orrenius, S. (1981) Toxic in-jury to isolated hepatocytes is not dependent on extracel-lular calcium. Science, 213, 1257-1259.
Trump, B.F. and Berezesky, I.K. (1995) Calcium-mediated cell injury and cell death. FASEB J., 9, 219-228.
Carafoli, E., Santella, L., Branca, D. and Brini, M. (2001) Generation, control, and processing of cellular calcium signals. Crit Rev Biochem. Mol Biol., 36, 107-260.
Berridge, M.J., Bootman, M.D. and Roderick, H.L. (2003) Calcium signaling: Dynamics, homeostasis and remod-eling. Nat Rev Mol Cell Biol, 4, 517-529.
Duchen, M.R. (2000) Mitochondria and calcium: From cell signaling to cell death. J. Physiol., 529 (Pt 1), 57-68.
Gunter, T.E., Yule, D.I., Gunter, K.K., Eliseev, R.A. and Salter, J.D. (2004) Calcium and mitochondria. FEBS Lett., 567, 96-102.
Hilgemann, D.W., Collins, A. and Matsuoka, S. (1992) Steady-state and dynamic properties of cardiac so-dium-calcium exchange: Secondary modulation by cyto-plasmic calcium and ATP. J. Gen. Physiol., 100, 933-961.
Bernardi, P. and Rasola, A. (2007) Calcium and cell death: The mitochondrial connection. Subcell. Biochem., 45, 481-506.
Crompton, M. (1999) The mitochondrial permeability transition pore and its role in cell death. J. Biochem., 341 (Pt 2), 233-249.
Lemasters, J.J., Theruvath, T.P., Zhong, Z. and Nieminen, A.L. (2009) Mitochondrial calcium and the permeability transition in cell death. Biochim. Biophys. Acta, 1787, 1395-1401.
Hardingham, G.E., Cruzalegui, F.H., Chawla, S. and Bading, H. (1998) Mechanisms controlling gene expression by nuclear calcium signals. Cell Calcium, 23, 131-134.
McKenzie, G.J. et al. (2005) Nuclear Ca2+ and CaM kinase IV specify hormonal- and Notch-responsiveness. J. Neurochem., 93, 171-185.
Papadia, S., Stevenson, P., Hardingham, N.R., Bading, H. and Hardingham, G.E. (2005) Nuclear Ca2+ and the camp response element-binding protein family mediate a late phase of activity-dependent neuroprotection. J. Neurosci., 25, 4279-4287.
Allbritton, N.L., Oancea, E., Kuhn, M.A. and Meyer, T. (1994) Source of nuclear calcium signals. Proc. Natl. Acad. Sci. USA, 91, 12458-12462.
Mazzanti, M., DeFelice, L.J., Cohen, J. and Malter, H. (1990) Ion channels in the nuclear envelope. Nature, 343, 764-767.
Sattler, R. and Tymianski, M. (2000) Molecular mecha-nisms of calcium-dependent excitotoxicity. J. Mol. Med., 78, 3-13.
Verkhratsky, A. (2002) The endoplasmic reticulum and neuronal calcium signaling. Cell Calcium, 32, 393-404.
Verkhratsky, A.J. and Petersen, O.H. (1998) Neuronal calcium stores. Cell Calcium, 24, 333-343.
Nikolaeva, M.A., Mukherjee, B. and Stys, P.K. (2005) Na+-dependent sources of intra-axonal Ca2+ release in rat optic nerve during in vitro chemical ischemia. J Neurosci, 25, 9960-9967.
Cantrell, A.R. and Catterall, W.A. (2001) Neuromodula-tion of Na+ channels: An unexpected form of cellular plasticity. Nat. Rev Neurosci., 2, 397-407.
Catterall, W.A., Goldin, A.L. and Waxman, S.G. (2003) International union of pharmacology. XXXIX. compen-dium of voltage-gated ion channels: Sodium channels. Pharmacol Rev., 55, 575-578.
Goldin, A.L. (2001) Resurgence of sodium channel re-search. Ann. Rev. Physiol., 63, 871-894.
Hille, B. (1992) Ionic channels of excitable membranes. Sinauer, Sunderland.
Waxman, S.G., Dib-Hajj, S., Cummins, T.R. and Black, J.A. (2000) Sodium channels and their genes: Dynamic expression in the normal nervous system, dysregulation in disease states (1). Brain Res., 886, 5-14.
Di Cera, E. et al. (1995) The Na [IMAGE] binding site of thrombin. J. Biol. Chem., 270, 22089-22092.
Yamashita, A., Singh, S.K., Kawate, T., Jin, Y. and Gouaux, E. (2005) Crystal structure of a bacterial homo-logue of Na+/Cl: Dependent neurotransmitter transporters. Nature, 437, 215-223.
Li, C., Capendeguy, O., Geering, K. and Horisberger, J.D. (2005) A third Na+-binding site in the sodium pump. Proc. Natl. Acad. Sci. USA, 102, 12706-12711.
Ogawa, H. and Toyoshima, C. (2002) Homology model-ing of the cation binding sites of Na+K+-ATPase. Proc. Natl. Acad. Sci. USA, 99, 15977-15982.