[en] We produced and analyzed mice deficient for Na/Ca exchanger 3 (NCX3), a protein that mediates cellular Ca(2+) efflux (forward mode) or Ca(2+) influx (reverse mode) and thus controls intracellular Ca(2+) concentration. NCX3-deficient mice (Ncx3(-/-)) present a skeletal muscle fiber necrosis and a defective neuromuscular transmission, reflecting the absence of NCX3 in the sarcolemma of the muscle fibers and at the neuromuscular junction. The defective neuromuscular transmission is characterized by the presence of electromyographic abnormalities, including low compound muscle action potential amplitude, a decremental response at low-frequency nerve stimulation, an incremental response, and a prominent postexercise facilitation at high-frequency nerve stimulation, as well as neuromuscular blocks. The analysis of quantal transmitter release in Ncx3(-/-) neuromuscular junctions revealed an important facilitation superimposed on the depression of synaptic responses and an elevated delayed release during high-frequency nerve stimulation. It is suggested that Ca(2+) entering nerve terminals is cleared relatively slowly in the absence of NCX3, thereby enhancing residual Ca(2+) and evoked and delayed quantal transmitter release during repetitive nerve stimulation. Our findings indicate that NCX3 plays an important role in vivo in the control of Ca(2+) concentrations in the skeletal muscle fibers and at the neuromuscular junction
Sokolow, S.; Université Libre de Bruxelles - ULB > IRIBHM-IBMM
Manto, M.; Université Libre de Bruxelles - ULB > Laboratory of Experimental Neurology
Gailly, P.; Université Catholique de Louvain - UCL > Department of Physiology
Molgó, J.; Centre National de la Recherche Scientifique, Gif-sur-Yvette, France > Institut Fédératif de Neurobiologie Alfred Fessard, Laboratoire de Neurobiologie Cellulaire et Moléculaire, Unité Propre de Recherche 9040
Vandebrouck, C.; Université Catholique de Louvain - UCL > Department of Physiology
Vanderwinden, J. M.; Université Libre de Bruxelles - ULB > Laboratory of Neurophysiology
Herchuelz, A.; Université Libre de Bruxelles - ULB > Laboratory of Pharmacology and Therapeutics
Schurmans, Stéphane ; Université de Liège - ULiège > Département de sciences fonctionnelles > Biochimie métabolique vétérinaire
Language :
English
Title :
Impaired neuromuscular transmission and skeletal muscle fiber necrosis in mice lacking Na/Ca exchanger 3
Publication date :
2004
Journal title :
Journal of Clinical Investigation
ISSN :
0021-9738
eISSN :
1558-8238
Publisher :
American Society for Clinical Investigation, Ann Arbor, United States - Michigan
Volume :
113
Pages :
265-273
Peer reviewed :
Peer Reviewed verified by ORBi
Name of the research project :
Belgian Telethon Action de Recherche Concertée grant (00/05-260)
Funders :
F.R.S.-FNRS - Fonds de la Recherche Scientifique [BE] ULB - Université Libre de Bruxelles [BE] FRSM - Fonds de la Recherche Scientifique Médicale [BE] AFM - Association Française contre les Myopathies [FR] FMRE - Fondation Médicale Reine Elisabeth [BE]
Nicoll, D.A., Longoni, S., and Philipson, K.D. 1990. Molecular cloning and functional expression of the cardiac sarcolemmal Na(+)-Ca2+ exchanger. Science. 250:562-565.
Nicoll, D.A., et al. 1996. Cloning of a third mammalian Na+-Ca2+ exchanger, NCX3. J. Biol. Chem. 271:24914-24921.
Li, Z., et al. 1994. Cloning of the NCX2 isoform of the plasma membrane Na(+)-Ca2+ exchanger. J. Biol. Chem. 269:17434-17439.
Quednau, B.D., Nicoll, D.A., and Philipson, K.D. 1997. Tissue specificity and alternative splicing of the Na+/Ca2+ exchanger isoforms NCX1, NCX2, and NCX3 in rat. Am. J. Physiol. 272:C1250-C1261.
Wakimoto, K., et al. 2000. Targeted disruption of Na+/Ca2+ exchanger gene leads to cardiomyocyte apoptosis and defects in heartbeat. J. Biol. Chem. 275:36991-36998.
Jeon, D., et al. 2003. Enhanced learning and memory in mice lacking Na+/Ca2+ exchanger 2. Neuron. 38:965-976.
Fraysse, B., et al. 2001. Expression of the Na(+)/Ca(2+) exchanger in skeletal muscle. Am. J. Physiol. Cell Physiol. 280:C146-C154.
Deval, E., Levitsky, D.O., Constantin, B., Raymond, G., and Cognard, C. 2000. Expression of the sodium/calcium exchanger in mammalian skeletal muscle cells in primary culture. Exp. Cell Res. 255:291-302.
De Backer, F., Vandebrouck, C., Gailly, P., and Gillis, J.M. 2002. Long-term study of Ca(2+) homeostasis and of survival in collagenase-isolated muscle fibres from normal and mdx mice. J. Physiol. 542:855-865.
Balnave, C.D., and Allen, D.G. 1998. Evidence for Na+/Ca2+ exchange in intact single skeletal muscle fibers from the mouse. Am. J. Physiol. 274:C940-C946.
Vanderwinden, J.M., Rumessen, J.J., Bernex, F., Schiffmann, S.N., and Panthier, J.J. 2000. Distribution and ultrastructure of interstitial cells of Cajal in the mouse colon, using antibodies to Kit and Kit(W-lacZ) mice. Cell Tissue Res. 302:155-170.
Vanderwinden, J.M., Rumessen, J.J., De Laet, M.H., Vanderhaeghen, J.J., and Schiffmann, S.N. 2000. CD34 immunoreactivity and interstitial cells of Cajal in the human and mouse gastrointestinal tract. Cell Tissue Res. 302:145-153.
Vilquin, J.T., et al. 1998. Evidence of mdx mouse skeletal muscle fragility in vivo by eccentric running exercise. Muscle Nerve. 21:567-576.
Lin, T.S., and Cheng, T.J. 1998. Stimulated single-fiber electromyography in the rat. Muscle Nerve. 21:482-489.
Gomez, C.M., et al. 1997. Slow-channel transgenic mice: a model of postsynaptic organellar degeneration at the neuromuscular junction. J. Neurosci. 17:4170-4179.
Verschuuren, J.J., Spaans, F., and De Baets, M.H. 1990. Single-fiber electromyography in experimental autoimmune myasthenia gravis. Muscle Nerve. 13:485-492.
Gooch, C.L., and Mosier, D.R. 2001. Stimulated single fiber electromyography in the mouse: techniques and normative data. Muscle Nerve. 24:941-945.
Oh, J. 1998. Principles of clinical electromyography case studies. Lippincott Williams & Wilkins. Baltimore, Maryland, USA. 604 pp.
Trontelj, J.V., and Stalberg, E. 1991. Single motor end-plates in myasthenia gravis and LEMS at different firing rates. Muscle Nerve. 14:226-232.
Sanders, D.B. 1992. The effect of firing rate on neuromuscular jitter in Lambert-Eaton myasthenic syndrome. Muscle Nerve. 15:256-258.
Minic, J., Chatonnet, A., Krejci, E., and Molgó, J. 2003. Butyrylcholinesterase and acetylcholinesterase activity and quantal transmitter release at normal and acetylcholinesterase knockout mouse neuromuscular junctions. Br. J. Pharmacol. 138:177-187.
McLachlan, E.M., and Martin, A.R. 1981. Non-linear summation of end-plate potentials in the frog and mouse. J. Physiol. 311:307-324.
Cruz, L.J., et al. 1985. Conus geographus toxins that discriminate between neuronal and muscle sodium channels. J. Biol. Chem. 260:9280-9288.
Ten Hage, L., et al. 2002. Effects of toxic extracts and purified borbotoxins from Prorocentrum borbonicum (Dinophyceae) on vertebrate neuromuscular junctions. Toxicon. 40:137-148.
Raymackers, J.M., et al. 2003. Consequence of parvalbumin deficiency in the mdx mouse: histological, biochemical and mechanical phenotype of a new double mutant. Neuromuscul. Disord. 13:376-387.
Zacharias, D.A., and Kappen, C. 1999. Developmental expression of the four plasma membrane calcium ATPase (Pmca) genes in the mouse. Biochim. Biophys. Acta. 1428:397-405.
Donoso, P., and Hidalgo, C. 1989. Sodium-calcium exchange in transverse tubules isolated from frog skeletal muscle. Biochim. Biophys. Acta. 978:8-16.
Hidalgo, C., Gonzalez, M.E., and Garcia, A.M. 1986. Calcium transport in transverse tubules isolated from rabbit skeletal muscle. Biochim. Biophys. Acta. 854:279-286.
Westerblad, H., and Allen, D.G. 1991. Changes of myoplasmic calcium concentration during fatigue in single mouse muscle fibers. J. Gen. Physiol. 98:615-635.
Lynch, G.S., Fary, C.J., and Williams, D.A. 1997. Quantitative measurement of resting skeletal muscle [Ca2+]i following acute and long-term downhill running exercise in mice. Cell Calcium. 22:373-383.
Blaustein, M.P., et al. 1991. Physiological roles of the sodium-calcium exchanger in nerve and muscle. Ann. N. Y. Acad. Sci. 639:254-274.
Luther, P.W., et al. 1992. Presynaptic localization of sodium/calcium exchangers in neuromuscular preparations. J. Neurosci. 12:4898-4904.
