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J. Biol. Chem., Vol. 279, Issue 53, 55850-55854, December 31, 2004

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Calbindin Independence of Calcium Transport in Developing Teeth Contradicts the Calcium Ferry Dogma^*

Chris I. Turnbull, Ken Looi, Jonathan E. Mangum¶, Michael Meyer||, Rod J. Sayer**, and Michael J. Hubbard¶

From the Departments of Biochemistry and ^**Physiology, University of Otago, PO Box 56, Dunedin 9001, New Zealand, the ^¶School of Dental Science, and Department of Paediatrics, The University of Melbourne, Melbourne, VIC 3052, Australia, and the ^||Physiologisches Institut, Ludwig Maximilians Universität München, Munich 80336, Germany

Cytosolic calcium-binding proteins termed calbindins are widely regarded as a key component of the machinery used to transport calcium safely across cells. Acting as mobile buffers, calbindins are thought to ferry calcium in bulk and simultaneously protect against its potentially cytotoxic effects. Here, we contradict this dogma by showing that teeth and bones were produced normally in null mutant mice lacking calbindin_28kDa. Structural analysis of dental enamel, the development of which depends critically on active calcium transport, showed that mineralization was unaffected in calbindin_28kDa-null mutants. An unchanged rate of calcium transport was verified by measurements of ⁴⁵Ca incorporation into developing teeth in vivo. In enamel-forming cells, the absence of calbindin_28kDa was not compensated by other cytosolic calcium-binding proteins as detectable by ⁴⁵Ca overlay, two-dimensional gel, and equilibrium binding analyses. Despite a 33% decrease in cytosolic buffer capacity, cytotoxicity was not evident in either the null mutant enamel or its formative cells. This is the first definitive evidence that calbindins are not required for active calcium transport, either as ferries or as facilitative buffers. Moreover, in challenging the broader notion of a cytosolic route for calcium, the findings support an alternative paradigm involving passage via calcium-tolerant organelles.

Received for publication, August 13, 2004 , and in revised form, October 19, 2004.

^* This work was supported in part by grants from Lottery Health Research and Health Research Council (HRC) of New Zealand (to M. J. H.) and by Deutsche Forschungsgemeinschaft Grant ME 1121/3 (to M. M.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Recipients of HRC Junior Health Research Awards.

Previously an HRC Senior Research Fellow. Now supported by the Melbourne Research Unit for Facial Disorders and Melbourne University. To whom correspondence should be addressed: Dept. of Paediatrics, Royal Children's Hospital, Flemington Rd., Melbourne, VIC 3052, Australia. Tel.: 61-3-9341-0449; Fax: 61-3-9341-0339; E-mail: mike.hubbard{at}unimelb.edu.au.

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