Kinetic Properties of Nicotinic Acid Adenine Dinucleotide Phosphate-induced Ca2+ Release

doi:10.1074/jbc.272.12.7669

Kinetic Properties of Nicotinic Acid Adenine Dinucleotide Phosphate-induced Ca²⁺ Release*

From the Department of Pharmacology, University of Oxford, Mansfield Road, Oxford OX1 3QT and the
^¶ School of Biochemistry, University of Birmingham, Birmingham B15 2TT, United Kingdom

^§ To whom correspondence should be addressed:
Dept. of Pharmacology, Mansfield Rd., Oxford OX1 3QT, UK.
Tel.: 44-1865-271890/271633; Fax: 44-1865-271853; E-mail: armando.genazzani{at}pharm.ox.ac.uk

Abstract

Three endogenous molecules have now been shown to release Ca²⁺ in the sea urchin egg: inositol trisphosphate (InsP₃), cyclic adenosine 5′-diphosphate ribose (cADPR), and nicotinic acid adenine dinucleotide phosphate (NAADP), a derivative of NADP. While the mechanism through which the first two molecules are able to release Ca²⁺ is established and well characterized with InsP₃ and cADPR-activating InsP₃ and ryanodine receptors, respectively, the newly described NAADP has been shown to release Ca²⁺ via an entirely different mechanism. The most striking feature of this novel Ca²⁺ release mechanism is its inactivation, since subthreshold concentrations of NAADP are able to fully and irreversibly desensitize the channel. In the present study we have investigated the fast kinetics of activation and inactivation of NAADP-induced Ca²⁺ release. NAADP was found to release Ca²⁺ in a biphasic manner, and such release was preceded by a pronounced latent period, which was inversely dependent on concentration. Moreover, the kinetic features of NAADP-induced Ca²⁺ release were not altered by pretreatment with low concentrations of NAADP, although the extent of Ca²⁺ release was greatly affected. Our data suggest that the inactivation of NAADP-induced Ca²⁺ release is an all-or-none phenomenon, and while some receptors have been fully inactivated, those that remain sensitive to NAADP do so without any change in kinetic features.

Footnotes

↵^‡ These authors have contributed equally to the manuscript.
↵* This work was supported by the Wellcome Trust, the Biotechnology and Biological Sciences Research Council (BBSRC), and the European Union. The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
↵¹ The abbreviations used are:

InsP₃

inositol trisphosphate

RyRs

ryanodine-sensitive Ca²⁺ channels

InsP₃Rs

InsP₃-sensitive Ca²⁺ channels

cADPR

cyclic adenosine 5′-diphosphate ribose

NAADP

nicotinic acid adenine dinucleotide phosphate.
- Received July 10, 1996.
- Revision received October 30, 1996.