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J. Biol. Chem., Vol. 283, Issue 9, 5486-5495, February 29, 2008

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SLC24A5 Encodes a trans-Golgi Network Protein with Potassium-dependent Sodium-Calcium Exchange Activity That Regulates Human Epidermal Melanogenesis^*

Rebecca S. Ginger¹, Sarah E. Askew, Richard M. Ogborne, Stephen Wilson, Dudley Ferdinando, Tony Dadd, Adrian M. Smith, Shubana Kazi, Robert T. Szerencsei, Robert J. Winkfein, Paul P. M. Schnetkamp, and Martin R. Green

From the Unilever Corporate Research, Colworth Science Park, Sharnbrook, Bedfordshire, MK44 1LQ, England, United Kingdom and the Department of Physiology and Biophysics, Hotchkiss Brain Institute, University of Calgary, Alberta, T2N 4N1 Canada

A non-synonymous single nucleotide polymorphism in the human SLC24A5 gene is associated with natural human skin color variation. Multiple sequence alignments predict that this gene encodes a member of the potassium-dependent sodium-calcium exchanger family denoted NCKX5. In cultured human epidermal melanocytes we show using affinity-purified antisera that native human NCKX5 runs as a triplet of 43 kDa on SDS-PAGE and is partially localized to the trans-Golgi network. Removal of the NCKX5 protein through small interfering RNA-mediated knockdown disrupts melanogenesis in human and murine melanocytes, causing a significant reduction in melanin pigment production. Using a heterologous expression system, we confirm for the first time that NCKX5 possesses the predicted exchanger activity. Site-directed mutagenesis of NCKX5 and NCKX2 in this system reveals that the non-synonymous single nucleotide polymorphism in SLC24A5 alters a residue that is important for NCKX5 and NCKX2 activity. We suggest that NCKX5 directly regulates human epidermal melanogenesis and natural skin color through its intracellular potassium-dependent exchanger activity.

Received for publication, September 7, 2007 , and in revised form, December 5, 2007.

^* 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.: 44-1234-248092; Fax: 44-1234-248010; E-mail address: rebecca.ginger{at}unilever.com.

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