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J. Biol. Chem., Vol. 281, Issue 23, 15923-15928, June 9, 2006
Messenger-specific Role for Nicotinic Acid Adenine Dinucleotide Phosphate in Neuronal Differentiation*![]() ![]() ![]() ![]() ![]() 1![]()
From the
Cells possess several Ca2+-mobilizing messengers, which couple stimulation at the cell surface by a multitude of extracellular cues to the regulation of intracellular Ca2+-sensitive targets. Recent studies suggest that agonists differentially select from this molecular palette to generate their characteristic Ca2+ signals but it is still unclear whether different messengers mediate different functions or whether they act in a redundant fashion. In this study, we compared the effects of nicotinic acid adenine dinucleotide phosphate (NAADP), a novel Ca2+-mobilizing messenger, with that of the prototypical messenger inositol trisphosphate on cytosolic Ca2+ levels and differentiation status of PC12 cells. We demonstrate that liposomal delivery of NAADP mediated release of Ca2+ from acidic Ca2+ stores and that this stimulus was sufficient to drive differentiation of the cells to a neuronal-like phenotype. In sharp contrast, cell fate was unaffected by more transient Ca2+ signals generated by inositol trisphosphate-evoked release of endoplasmic reticulum Ca2+ stores. Our data establish for the first time (i) the presence of novel NAADP-sensitive Ca2+ stores in PC12 cells, (ii) a role for NAADP in differentiation, and (iii) that Ca2+-dependent function can be messenger-specific. Thus, differential recruitment of intracellular Ca2+-mobilizing messengers and their target Ca2+ stores may represent a robust means of maintaining stimulus fidelity in the control of Ca2+-dependent cell function.
Received for publication, March 9, 2006 , and in revised form, March 24, 2006. * This work was supported by grants from the National Institutes of Health (to N. J. D.) and the Wellcome Trust, UK (to S. P.). 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. 1 To whom correspondence should be addressed: The Old Squash Courts, Dept. of Physiology, University College London, Gower St., London WC1E 6BT, UK. Tel.: 44-207-679-6540; Fax: 44-207-813-0530; E-mail: patel.s{at}ucl.ac.uk.
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