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J. Biol. Chem., Vol. 282, Issue 20, 15302-15311, May 18, 2007

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NAADP Controls Cross-talk between Distinct Ca²⁺ Stores in the Heart^*

From the Department of Pharmacology, University of Oxford, Mansfield Road, Oxford OX1 3QT, United Kingdom

In cardiac muscle the sarcoplasmic reticulum (SR) plays a key role in the control of contraction, releasing Ca²⁺ in response to Ca²⁺ influx across the sarcolemma via voltage-gated Ca²⁺ channels. Here we report evidence for an additional distinct Ca²⁺ store and for actions of nicotinic acid adenine dinucleotide phosphate (NAADP) to mobilize Ca²⁺ from this store, leading in turn to enhanced Ca²⁺ loading of the SR. Photoreleased NAADP increased Ca²⁺ transients accompanying stimulated action potentials in ventricular myocytes. The effects were prevented by bafilomycin A (an H⁺-ATPase inhibitor acting on acidic Ca²⁺ stores), by desensitizing concentrations of NAADP, and by ryanodine and thapsigargin to suppress SR function. Bafilomycin A also suppressed staining of acidic stores with Lysotracker Red without affecting SR integrity. Cytosolic application of NAADP by means of its membrane permeant acetoxymethyl ester increased myocyte contraction and the frequency and amplitude of Ca²⁺ sparks, and these effects were inhibited by bafilomycin A. Effects of NAADP were associated with an increase in SR Ca²⁺ load and appeared to be regulated by -adrenoreceptor stimulation. The observations are consistent with a novel role for NAADP in cardiac muscle mediated by Ca²⁺ release from bafilomycin-sensitive acidic stores, which in turn enhances SR Ca²⁺ release by increasing SR Ca²⁺ load.

Received for publication, December 5, 2006 , and in revised form, March 16, 2007.

^* This work is supported by The Wellcome trust. 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. Tel.: 44-1865-271614; Fax: 44-1865-271853; E-mail: michiko.yamasaki{at}pharmacology.oxford.ac.uk.

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