title: SLC24A5 encodes a trans-Golgi network protein with potassium-dependent sodium-calcium exchange activity that regulates human epidermal melanogenesis.
abstract: 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 approximately 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.
authors.affiliation: Unilever Corporate Research, Colworth Science Park, Sharnbrook, Bedfordshire, MK44 1LQ, England, United Kingdom. rebecca.ginger@unilever.com
authors.forename: Rebecca S
authors.initials: RS
authors.lastname: Ginger
authors.forename: Sarah E
authors.initials: SE
authors.lastname: Askew
authors.forename: Richard M
authors.initials: RM
authors.lastname: Ogborne
authors.forename: Stephen
authors.initials: S
authors.lastname: Wilson
authors.forename: Dudley
authors.initials: D
authors.lastname: Ferdinando
authors.forename: Tony
authors.initials: T
authors.lastname: Dadd
authors.forename: Adrian M
authors.initials: AM
authors.lastname: Smith
authors.forename: Shubana
authors.initials: S
authors.lastname: Kazi
authors.forename: Robert T
authors.initials: RT
authors.lastname: Szerencsei
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Winkfein
authors.forename: Paul P M
authors.initials: PP
authors.lastname: Schnetkamp
authors.forename: Martin R
authors.initials: MR
authors.lastname: Green
mesh_terms: D000818:Animals; D017920:Antiporters / Q000235:genetics / Q000378:metabolism*; D002118:Calcium / Q000378:metabolism; D045744:Cell Line, Tumor; D006056:Golgi Apparatus / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D017136:Ion Transport / Q000502:physiology; D008297:Male; D008543:Melanins / Q000096:biosynthesis* / Q000235:genetics; D008544:Melanocytes / Q000166:cytology / Q000378:metabolism*; D051379:Mice; D010858:Pigmentation / Q000502:physiology*; D020641:Polymorphism, Single Nucleotide; D011188:Potassium / Q000378:metabolism; D012964:Sodium / Q000378:metabolism; D019831:Sodium-Calcium Exchanger / Q000235:genetics / Q000378:metabolism
chemical_list: D017920:Antiporters; D008543:Melanins; C506584:SLC24A5 protein, human; D019831:Sodium-Calcium Exchanger; C074530:potassium-dependent sodium-calcium exchanger; D012964:Sodium; D011188:Potassium; D002118:Calcium