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J. Biol. Chem., Vol. 282, Issue 35, 25259-25269, August 31, 2007

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Reconstitution and Characterization of a Nicotinic Acid Adenine Dinucleotide Phosphate (NAADP)-sensitive Ca²⁺ Release Channel from Liver Lysosomes of Rats^*

From the Department of Pharmacology and Toxicology, Medical College of Virginia, Virginia Commonwealth University, Richmond, Virginia 23298

Nicotinic acid adenine dinucleotide phosphate (NAADP) is capable of inducing global Ca²⁺ increases via a lysosome-associated mechanism, but the mechanism mediating NAADP-induced intracellular Ca²⁺ release remains unclear. The present study reconstituted and characterized a lysosomal NAADP-sensitive Ca²⁺ release channel using purified lysosomes from rat liver. Furthermore, the identity of lysosomal NAADP-sensitive Ca²⁺ release channels was also investigated. It was found that NAADP activates lysosomal Ca²⁺ release channels at concentrations of 1 nM to 1 µM, but this activating effect of NAADP was significantly reduced when the concentrations used increased to 10 or 100 µM. Either activators or blockers of Ca²⁺ release channels on the sarcoplasmic reticulum (SR) had no effect on the activity of these NAADP-activated Ca²⁺ release channels. Interestingly, the activity of this lysosomal NAADP-sensitive Ca²⁺release channel increased when the pH in cis solution decreased, but it could not be inhibited by a lysosomal H⁺-ATPase antagonist, bafilomycin A1. However, the activity of this channel was significantly inhibited by plasma membrane L-type Ca²⁺ channel blockers such as verapamil, diltiazem, and nifedipine, or the nonselective Ca²⁺,Na⁺ channel blocker, amiloride. In addition, blockade of TRP-ML1 (transient receptor potential-mucolipin 1) protein by anti-TRP-ML1 antibody markedly attenuated NAADP-induced activation of these lysosomal Ca²⁺ channels. These results for the first time provide direct evidence that a NAADP-sensitive Ca²⁺ release channel is present in the lysosome of native liver cells and that this channel is associated with TRP-ML1, which is different from ER/SR Ca²⁺ release channels.

Received for publication, February 23, 2007 , and in revised form, July 2, 2007.

^* This work was supported by National Institutes of Health Grants HL057244-09 and HL075316-01. 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: Dept. of Pharmacology and Toxicology, Medical College of Virginia, VA Commonwealth University, 410 North 12th St., P.O. Box 980613, Richmond, VA 23298. Tel.: 804-828-4793; Fax: 804-828-2117; E-mail: pli{at}vcu.edu.

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