SLC24A5 encodes a trans-Golgi network protein with potassium-dependent sodium-calcium exchange activity that regulates human epidermal melanogenesis.
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.
Ginger
Rebecca S
RS
Unilever Corporate Research, Colworth Science Park, Sharnbrook, Bedfordshire, MK44 1LQ, England, United Kingdom. rebecca.ginger@unilever.com
Askew
Sarah E
SE
Ogborne
Richard M
RM
Wilson
Stephen
S
Ferdinando
Dudley
D
Dadd
Tony
T
Smith
Adrian M
AM
Kazi
Shubana
S
Szerencsei
Robert T
RT
Winkfein
Robert J
RJ
Schnetkamp
Paul P M
PP
Green
Martin R
MR
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
D017920:Antiporters; D008543:Melanins; C506584:SLC24A5 protein, human; D019831:Sodium-Calcium Exchanger; C074530:potassium-dependent sodium-calcium exchanger; D012964:Sodium; D011188:Potassium; D002118:Calcium