The Role of Intracellular Calcium Signaling in Motoneuron Function and Disease

  • Bernhard U. Keller


Precise motoneuron performance is essential for many aspects of nervous system function, including swallowing, breathing, locomotion and movement of the tongue. Motoneurones are also particularly vulnerable during human amyotrophic lateral sclerosis (ALS) and corresponding animal models of this neurodegenerative disease. While some motoneuron populations including spinal and brain stem motoneurones are particularly impaired, other populations like oculomotor neurones are largely resistant to ALS-related degeneration. This is a well-known phenomenon in advanced clinical stages of human ALS, but also in related animal models of motoneuron disease (Elliot and Snider, 1995; Ince et al., 1993; Reiner et al., 1995). Selective vulnerability of motoneurones has been closely linked to cell-specific disruptions of calcium signaling, but the underlying cellular and molecular events are only little understood. Recent progress in the experimental analysis of calcium signaling has permitted investigations of calcium regulation in different neuron types, in particular in selectively vulnerable and resistant motoneuron populations in animal models of neurodegenerative disease. This chapter provides an overview of recent advances in this field with an emphasis on calcium signal cascades in ALS-related motoneuron damage. By avoiding technical specialities that can be taken from the reference list, this article is aimed at readers with a background in basic academic or clinical research without specific knowledge about motoneuron physiology or microfluorometric calcium measurements.


Amyotrophic Lateral Sclerosis Motoneuron Disease Spinal Motoneurones Extrusion Rate Nucleus Hypoglossus 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. Abdel-Hamid, K.M. and Baimbridge, K.G., 1997, The effects of artificial calcium buffers on calcium responses and glutamate-mediated excitotoxicity in cultured hippocampal neurons, Neuroscience 81, 673–687.PubMedCrossRefGoogle Scholar
  2. Alexianu, M.E., Ho, B.K., Mohamed, A.H., La, B.V., Smith, R.G. and Appel, S.H., 1994, The role of calcium-binding proteins in selective motoneuron vulnerability in amyotrophic lateral sclerosis, Ann. Neurol. 36, 846–858.PubMedCrossRefGoogle Scholar
  3. Alexianu, M.E., Robbins, E., Carswell, S. and Appel, S.H., 1998, 1Alpha, 25 dihydroxyvit-amin D3-dependent up-regulation of calcium-binding proteins in motoneuron cells, J. Neurosci. Res. 51, 58–66.PubMedCrossRefGoogle Scholar
  4. Appel, S.H., Smith, R.G., Alexianu, M., Siklos, L., Engelhardt, J., Colom, L.V. and Stefani, E., 1995, Increased intracellular calcium triggered by immune mechanisms in amyotrophic lateral sclerosis, Clin. Neurosci. 3, 368–374.PubMedGoogle Scholar
  5. Baimbridge, K.G., Celio, M.R. and Rogers, J.H., 1992, Calcium-binding proteins in the nervous system, Trends Neurosci. 15, 303–308.PubMedCrossRefGoogle Scholar
  6. Bayliss, D.A., Viana, F., Talley, E.M. and Berger, A.J., 1997, Neuromodulation of hypoglossal motoneurons: Cellular and developmental mechanisms, Respir. Physiol. 110(2–3), 139–150.PubMedCrossRefGoogle Scholar
  7. Blaustein, M.P., 1988, Calcium transport and buffering in neurons, Trends Neurosci. 11, 438–443.PubMedCrossRefGoogle Scholar
  8. Bruijn, L.I., Housewaert, M.K., Kato, S., Anderson, K.L., Anderson, S.D., Ohama, E., Reaume, A.G., Scott, R.W. and Cleveland, D.W., 1998, Aggregation and motor neuron toxicity of an ALS-linked SOD1 mutant independent from wild-type SOD1, Science 281, 1851–1854.PubMedCrossRefGoogle Scholar
  9. Celio, M.R., 1990, Calbindin and parvalbumin in the rat nervous system, Neuroscience 35, 375–475.PubMedCrossRefGoogle Scholar
  10. Chad, J., 1989, Inactivation of calcium channels, Comp. Biochem. Physiol. A 93, 95–105.PubMedCrossRefGoogle Scholar
  11. Choi, D.W., 1988, Glutamate neurotoxicity and diseases of the nervous system, Neuron 1, 623–634.PubMedCrossRefGoogle Scholar
  12. Christakos, S., Barletta, F., Huening, M., Kohut, J. and Raval-Pandya, M., 2000, Activation of programmed cell death by calcium: Protection against cell death by the calcium binding protein, Calbindin 28K, this book.Google Scholar
  13. DePaul, R., Abbs, J.H., Caligiuri, M., Gracco, V.L. and Brooks, B.R., 1988, Hypoglossal, trigeminal, and facial motoneuron involvement in amyotrophic lateral sclerosis, Neurology 38, 281–283.PubMedCrossRefGoogle Scholar
  14. Elliot, J.L. and Snider, W.D., 1995, Parvalbumin is a marker of ALS-resistant motor neurons, Neuroreport 6(3), 449–452.CrossRefGoogle Scholar
  15. Fierro, L. and Llano, I., 1996, High endogenous calcium buffering in Purkinje cells from rat cerebellar slices, J. Physiol. 496, 617–625.PubMedGoogle Scholar
  16. Frermann, D., Keller, B.U. and Richter, D.W., 1999, Calcium oscillations in rhythmically active respiratory neurones in the brainstem of mouse, J. Physiol. (Lond.) 515, 119–131.CrossRefGoogle Scholar
  17. Gurney, M.E., Cuttings, F.B., Zhai, P., Doble, A., Taylor, C.P., Andrus, P.K. and Hal, E.D., 1996, Benefit of vitamin E, riluzole, and gabapentin in a transgenic model of familial amyotrophic laterale sclerosis, Ann. Neurol. 39, 147–157.PubMedCrossRefGoogle Scholar
  18. Helmchen, F., Imoto, K. and Sakmann, B., 1996, Ca2+ buffering and action potential-evoked Ca2+ signaling in dendrites of pyramidal neurons, Biophys. J. 70, 1069–1081.PubMedCrossRefGoogle Scholar
  19. Helmchen, F., Borst, J.G. and Sakmann, B., 1997, Calcium dynamics associated with a single action potential in a CNS presynaptic terminal, Biophys. J. 72, 1458–1471.PubMedCrossRefGoogle Scholar
  20. Ho, B.K., Alexianu, M.E., Colom, L.V., Mohamed, A.H., Serrano, F. and Appel, S.H., 1996, Expression of calbindin-D28K in motoneuron hybrid cells after retroviral infection with calbindin-D28K cDNA prevents amyotrophic lateral sclerosis IgG-mediated cytotoxicity, Proc. Natl. Acad. Sci. USA 93, 6796–6801.PubMedCrossRefGoogle Scholar
  21. Ince, P., Stout, N., Shaw, P., Slade, J., Hunziker, W., Heizmann, C.W. and Baimbridge, K.G., 1993, Parvalbumin and calbindin D-28k in the human motor system and in motoneuron disease, Neuropathol. Appl. Neurobiol. 19(4), 291–299.PubMedCrossRefGoogle Scholar
  22. Keller, B.U., Konnerth, A. and Yaari, Y., 1991, Patch clamp analysis of excitatory synaptic currents in granule cells of rat hippocampus, J. Physiol. 435, 275–293.PubMedGoogle Scholar
  23. Klapstein, G.J., Vietla, S., Lieberman, D.N., Gray, P.A., Airaksinen, M.S., Thoenen, H, Meyer, M. and Mody, I., 1998, Calbindin-D28 fails to protect hippocampal neurons against ischemia in spite of its cytoplasmic calcium buffering properties: Evidence from calbindin-D28k knockout mice, Neuroscience 85(2), 361–373.PubMedCrossRefGoogle Scholar
  24. Klingauf, J. and Neher, E., 1997, Modelling buffered Ca++ diffusion near the membrane: Implications for secretion in neuroendocrine cells, Biophys. J. 72, 674–690.PubMedCrossRefGoogle Scholar
  25. Krieger, C., Jones, K., Kim, S.U. and Eisen, A.A., 1994, The role of intracellular free calcium in motor neuron disease, J. Neurol. Sci. 124, 27–32.PubMedCrossRefGoogle Scholar
  26. Krieger, C., Lanius, R.A., Pelech, S.L. and Shaw, CA., 1996, Amyotrophic lateral sclerosis: The involvement of intracellular Ca2+ and protein kinase C, Trends Pharmacol. Sci. 17, 114–120.PubMedCrossRefGoogle Scholar
  27. Ladewig, T. and Keller, B.U., 1998, Calcium imaging in rhythmically active motoneurones in the nucleus hypoglossus from mouse, Pflügers Archi 435, R62.Google Scholar
  28. Ladewig, T. and Keller, B.U., 2000, Simultaneous patch clamp recording and calcium imaging in a rhythmically active neuronal network in the brainstem slice preparation from mouse, Pflügers Arch. 440, 322–332.PubMedGoogle Scholar
  29. Lev-Tov, A. and O’Donovan, M.J., 1995, Calcium imaging of motoneuron activity in the en-bloc spinal cord preparation of the neonatal rat, J. Neurophysiol. 74(3), 1324–1334.PubMedGoogle Scholar
  30. Lips, M.B. and Keller, B.U., 1998, Endogenous calcium buffering in motoneurones of the nucleus hypoglossus from mouse, J. Physiol. 511, 105–117.PubMedCrossRefGoogle Scholar
  31. Lips, M.B. and Keller, B.U., 1999, Activity-related calcium dynamics in motoneurones of the nucleus hypoglossus from mouse, J. Neurophys. 82(6), 2936–2946.Google Scholar
  32. McBurney, R.N. and Neering, I.R., 1987, Neuronal calcium homeostasis, Trends Neurosci. 10, 164–169.CrossRefGoogle Scholar
  33. McMahon, A., Wong, B.S., Iacopino, A.M., Ng, M.C., Chi, S. and German, D.C., 1998, Calbindin-D28k buffers intracellular calcium and promotes resistance to degeneration in PC12 cells, Brain Res. Mol. Brain Res. 54, 56–63.PubMedCrossRefGoogle Scholar
  34. Medina, L., Figueredo-Crdenas, G., Rothstein, J.D. and Reiner, A., 1996, Differential abundance of glutamate transporter subtypes in amyotrophic lateral scleroses (ALS)-vulnarable versus ALS-resistant brain stem motor cell groups, Exp. Neurol. 142, 287–295.PubMedCrossRefGoogle Scholar
  35. Meldrum, B. and Garthwaite, J., 1990, Exciatory amino acid neurotoxicity and neurodegenerative disease, Trends Pharmacol. Sci. 11, 379–387.PubMedCrossRefGoogle Scholar
  36. Morrison, B.M. and Morrison, J.H., 1998, Amyotrophic lateal sclerosis associated with mutations in superoxide dismutase: A putative mechanism of degeneration, Brain Res. Rev. 29, 121–135.CrossRefGoogle Scholar
  37. Nägerl, U.V. and Mody, I., 1998, Calcium-dependent inactivation of high-threshold calcium currents in human dentate gyrus granule cells, J. Physiol. (Lond.) 509, 39–45.CrossRefGoogle Scholar
  38. Neher, E., 1986, Concentration profiles of intracellular calcium in the presence of a diffusable chelator, Exp. Brain Res., Series 14, 80–96.Google Scholar
  39. Neher, E., 1995, The use of fura-2 for estimating Ca2+ buffers and Ca2+ fluxes, Neuropharmacology 34, 1423–1442.PubMedCrossRefGoogle Scholar
  40. Neher, E. and Augustine, G.J., 1992, Calcium gradients and buffers in bovine chromaffin cells, J. Physiology 450, 273–301.Google Scholar
  41. Palecek, J., Lips, M.B. and Keller, B.U., 1999, Calcium dynamics and buffering in motoneurons of the mouse spinal cord, J. Physiol. 520(2), 486–502.CrossRefGoogle Scholar
  42. Reiner, A., Medina, L., Figueredo, C.G. and Anfinson, S., 1995, Brainstem motoneuron pools that are selectively resistant in amyotrophic lateral sclerosis are preferentially enriched in parvalbumin: Evidence from monkey brainstem for a calcium-mediated mechanism in sporadic ALS, Exp. Neurol. 131, 239–250.PubMedCrossRefGoogle Scholar
  43. Roberts, W.M., 1994, Localization of calcium signals by a mobile calcium buffer in frog saccular hair cells, J. Neurosci. 14, 3246–3262.PubMedGoogle Scholar
  44. Rothstein, J.D. and Kuncl, R.W., 1995, Neuroprotective strategies in a model of chronic glutamate-mediated motor neuron toxicity, J. Neurochem. 65, 643–651.PubMedCrossRefGoogle Scholar
  45. Rothstein, J.D., Martin, L.J. and Kuncl, R.W., 1992, Decreased glutamate transport by the brain and spinal cord in amyotrophic lateral sclerosis, New Engl. J. Med. 326, 1464–1468.PubMedCrossRefGoogle Scholar
  46. Rothstein, J.D., Van Kammen, M., Levey, A.I., Martin, L.J. and Kuncl, R.W., 1995, Selective loss of glial glutamate transporter GLT-1 in amyotrophic lateralsclerosis, Ann. Neurol. 38, 73–84.PubMedCrossRefGoogle Scholar
  47. Roy, J., Minotti, S., Dong, L., Figlewicz, D.D. and Durham, H.D., 1998, Glutamate potentiates the toxicity of mutant Cu/Zn-superoxide dismutase in motor neurones by postsynaptic calcium-dependent mechanisms, J. Neurosci. 18(23), 9673–9684.PubMedGoogle Scholar
  48. Schafer, B.W. and Heizmann, C.W., 1996, The S100 family of EF-handed calcium binding proteins: Function and pathology, Trends Biochem. Sci. 21, 134–140.PubMedGoogle Scholar
  49. Shaw, P.J. and Ince, P.G., 1997, Glutamate, excitotoxicity and amyotrophic lateral sclerosis, J. Neurol. 244, 3–14.CrossRefGoogle Scholar
  50. Shaw, P.J., Williams, T.L., Slade, J.Y., Eggett, E.Y. and Ince, P.G., 1999, Low expression of GluR2 Ampa receptor subunit protein by human motor neurons, Neuroreport 10(2), 261–265.PubMedCrossRefGoogle Scholar
  51. Siklos, L., Engelhardt, G.I., Alexianu, M.E., Siddique, T. and Appel, S.H., 1998, Intracellular calcium parallels motoneuron degeneration in SOD-1 mutant mice, J. Neuropathol. Exp. Neurol. 57(6), 571–587.PubMedCrossRefGoogle Scholar
  52. Smith, J.C., Ellenberger, H.H., Ballanyi, K., Richter, D.W. and Feldman, J.L., 1991, Pre-Botzinger complex: A brainstem region that may generate respiratory rhythm in mammals, Science 254, 726–729.PubMedCrossRefGoogle Scholar
  53. Smith, R.G., Hamilton, S., Hofmann, F., Schneider, T., Nastainczyk, W, Birnbaumer, L., Stefani, E. and Appel, S.H., 1992, Serum antibodies to L-type calcium channels in patients with amyotrophic laterale sclerosis, New Engl. J. Med. 327, 1721–1728.PubMedCrossRefGoogle Scholar
  54. Trotti, D., Rolfs, A., Danbolt, N.C., Brown, R.H. and Hediger, M.A., 1999, SOD1 mutants linked to amyotrophic lateral sclerosis selectively inactivate a glial glutamate transporter, Nat. Neurosci. 2(5), 427–433.PubMedCrossRefGoogle Scholar
  55. Tu, P.H., Raju, O., Robinson, K.A., Gurney, M.E., Trojanowski, J.Q. and Lee, M.Y., 1996, Transgenic mice carrying a human mutant Superoxid dismutase transgene develop neuronal cytoskeletal pathology resembling human amyotrophic lateral sclerosis lesions, Proc. Natl. Acad. Sci. USA 93, 3155–3160.PubMedCrossRefGoogle Scholar
  56. Tymianski, M., Charlton, M.P, Carlen, P.L. and Tator, C.H., 1994, Properties of neuroprotective cell-permeant Ca2+ chelators: Effects on [Ca2+]i and glutamate neurotoxicity in vitro, J. Neurophysiol. 72, 1973–1992PubMedGoogle Scholar
  57. Vanselow, B. and Keller, B.U., 2000, A quantitative evaluation of calcium dynamics and buffering in oculomotor neurones from mouse, J. Physiol. 522, 433–445.CrossRefGoogle Scholar
  58. Viana, F., Bayliss, D.A. and Berger, A.J., 1993a, Calcium conductances and their role in the firing behavior of neonatal rat hypoglossal motoneurons, J. Neurophysiol. 69, 2137–2149.PubMedGoogle Scholar
  59. Viana, F., Bayliss, D.A. and Berger, A.J., 1993b, Multiple potassium conductances and their role in action potential repolarization and repetitive firing behavior of neonatal rat hypoglossal motoneurons, J. Neurophysiol. 69, 2150–2163.PubMedGoogle Scholar
  60. Williamson, T.L., Bruijn, L.I., Zhu, Q., Anderson, K.L., Anderson, S.D., Julien, J. and Cleveland, D.W., 1998, Absence of neurofilaments reduces the selective vulnerability of motor neurons and slows disease caused by a familial amyotrophic lateral sclerosis-linked superoxide dismutase 1 mutant, Proc. Natl. Acad. Sci. USA 95, 9631–9636.PubMedCrossRefGoogle Scholar
  61. Zhou, Z. and Neher, E., 1993, Mobile and immobile calcium buffers in bovine adrenal cells, J. Physiol. 469, 245–273.PubMedGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2000

Authors and Affiliations

  • Bernhard U. Keller
    • 1
  1. 1.Zentrum Physiologie und PathophysiologieUniversität GöttingenGöttingenGermany

Personalised recommendations