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...
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| Veröffentlicht in: | The Journal of biological chemistry 2008-02, Vol.283 (9), p.5486-5495 |
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| creator | Ginger, Rebecca S. Askew, Sarah E. Ogborne, Richard M. Wilson, Stephen Ferdinando, Dudley Dadd, Tony Smith, Adrian M. Kazi, Shubana Szerencsei, Robert T. Winkfein, Robert J. Schnetkamp, Paul P.M. Green, Martin R. |
| description | 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. |
| doi_str_mv | 10.1074/jbc.M707521200 |
| format | Article |
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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.</description><identifier>ISSN: 0021-9258</identifier><identifier>EISSN: 1083-351X</identifier><identifier>DOI: 10.1074/jbc.M707521200</identifier><identifier>PMID: 18166528</identifier><language>eng</language><publisher>United States: Elsevier Inc</publisher><subject>Animals ; Antiporters - genetics ; Antiporters - metabolism ; Calcium - metabolism ; Cell Line, Tumor ; Golgi Apparatus - genetics ; Golgi Apparatus - metabolism ; Humans ; Ion Transport - physiology ; Male ; Melanins - biosynthesis ; Melanins - genetics ; Melanocytes - cytology ; Melanocytes - metabolism ; Mice ; Pigmentation - physiology ; Polymorphism, Single Nucleotide ; Potassium - metabolism ; Sodium - metabolism ; Sodium-Calcium Exchanger - genetics ; Sodium-Calcium Exchanger - metabolism</subject><ispartof>The Journal of biological chemistry, 2008-02, Vol.283 (9), p.5486-5495</ispartof><rights>2008 © 2008 ASBMB. 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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.</description><subject>Animals</subject><subject>Antiporters - genetics</subject><subject>Antiporters - metabolism</subject><subject>Calcium - metabolism</subject><subject>Cell Line, Tumor</subject><subject>Golgi Apparatus - genetics</subject><subject>Golgi Apparatus - metabolism</subject><subject>Humans</subject><subject>Ion Transport - physiology</subject><subject>Male</subject><subject>Melanins - biosynthesis</subject><subject>Melanins - genetics</subject><subject>Melanocytes - cytology</subject><subject>Melanocytes - metabolism</subject><subject>Mice</subject><subject>Pigmentation - physiology</subject><subject>Polymorphism, Single Nucleotide</subject><subject>Potassium - metabolism</subject><subject>Sodium - metabolism</subject><subject>Sodium-Calcium Exchanger - genetics</subject><subject>Sodium-Calcium Exchanger - metabolism</subject><issn>0021-9258</issn><issn>1083-351X</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2008</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNp1kU9vEzEQxS0EoiFw5QgWB24bbO-feI9RFFqkFCrSStysWe_srsvuOrW9Df0efGAcJVJP-DKS5zdvRu8R8p6zBWfL7Mt9pRfXS7bMBReMvSAzzmSapDn_9ZLMGBM8KUUuL8gb7-9ZfFnJX5MLLnlR5ELOyN_ddi2yVU43o7Y1ego0OBh9cmn71tDvGA7W_aY3zgY0Iz2Y0NEbG8B7Mw1JjXscaxwD3dn6-LGGXsdKN390B2OLdKWDeTThid52EOhPbKceQlxzNQ0w0s3e1OgG6Ok19jDaFkf0xr8lrxroPb471zm5-7q5XV8l2x-X39arbaJzVoZEVBxBFktZaoAmlZqzow2lTHXaZEVZNRkWZQk5VA1DJpYphxTLDHIOkEudzsnnk-7e2YcJfVCD8Rr7eAraySvBZFbILIvg4gRqZ7132Ki9MwO4J8WZOuagYg7qOYc48OGsPFUD1s_42fgIfDoBnWm7g3GoKmN1h4OKTVWqPJNFhD6eoAasgtYZr-52gvGUMVmIY9JzIk8ERpseDTrltcFRYx0ldVC1Nf878R_W2KyS</recordid><startdate>20080229</startdate><enddate>20080229</enddate><creator>Ginger, Rebecca S.</creator><creator>Askew, Sarah E.</creator><creator>Ogborne, Richard M.</creator><creator>Wilson, Stephen</creator><creator>Ferdinando, Dudley</creator><creator>Dadd, Tony</creator><creator>Smith, Adrian M.</creator><creator>Kazi, Shubana</creator><creator>Szerencsei, Robert T.</creator><creator>Winkfein, Robert J.</creator><creator>Schnetkamp, Paul P.M.</creator><creator>Green, Martin R.</creator><general>Elsevier Inc</general><general>American Society for Biochemistry and Molecular Biology</general><scope>6I.</scope><scope>AAFTH</scope><scope>FBQ</scope><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7QP</scope><scope>7TM</scope></search><sort><creationdate>20080229</creationdate><title>SLC24A5 Encodes a trans-Golgi Network Protein with Potassium-dependent Sodium-Calcium Exchange Activity That Regulates Human Epidermal Melanogenesis</title><author>Ginger, Rebecca S. ; Askew, Sarah E. ; Ogborne, Richard M. ; Wilson, Stephen ; Ferdinando, Dudley ; Dadd, Tony ; Smith, Adrian M. ; Kazi, Shubana ; Szerencsei, Robert T. ; Winkfein, Robert J. ; Schnetkamp, Paul P.M. ; Green, Martin R.</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c509t-2b1ea86789caaf38c105212983c3f469bf4e699a5abf0e02731a3e94a51aa58c3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2008</creationdate><topic>Animals</topic><topic>Antiporters - genetics</topic><topic>Antiporters - metabolism</topic><topic>Calcium - metabolism</topic><topic>Cell Line, Tumor</topic><topic>Golgi Apparatus - genetics</topic><topic>Golgi Apparatus - metabolism</topic><topic>Humans</topic><topic>Ion Transport - physiology</topic><topic>Male</topic><topic>Melanins - biosynthesis</topic><topic>Melanins - genetics</topic><topic>Melanocytes - cytology</topic><topic>Melanocytes - metabolism</topic><topic>Mice</topic><topic>Pigmentation - physiology</topic><topic>Polymorphism, Single Nucleotide</topic><topic>Potassium - metabolism</topic><topic>Sodium - metabolism</topic><topic>Sodium-Calcium Exchanger - genetics</topic><topic>Sodium-Calcium Exchanger - metabolism</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Ginger, Rebecca S.</creatorcontrib><creatorcontrib>Askew, Sarah E.</creatorcontrib><creatorcontrib>Ogborne, Richard M.</creatorcontrib><creatorcontrib>Wilson, Stephen</creatorcontrib><creatorcontrib>Ferdinando, Dudley</creatorcontrib><creatorcontrib>Dadd, Tony</creatorcontrib><creatorcontrib>Smith, Adrian M.</creatorcontrib><creatorcontrib>Kazi, Shubana</creatorcontrib><creatorcontrib>Szerencsei, Robert T.</creatorcontrib><creatorcontrib>Winkfein, Robert J.</creatorcontrib><creatorcontrib>Schnetkamp, Paul P.M.</creatorcontrib><creatorcontrib>Green, Martin R.</creatorcontrib><collection>ScienceDirect Open Access Titles</collection><collection>Elsevier:ScienceDirect:Open Access</collection><collection>AGRIS</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>Calcium & Calcified Tissue Abstracts</collection><collection>Nucleic Acids Abstracts</collection><jtitle>The Journal of biological chemistry</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Ginger, Rebecca S.</au><au>Askew, Sarah E.</au><au>Ogborne, Richard M.</au><au>Wilson, Stephen</au><au>Ferdinando, Dudley</au><au>Dadd, Tony</au><au>Smith, Adrian M.</au><au>Kazi, Shubana</au><au>Szerencsei, Robert T.</au><au>Winkfein, Robert J.</au><au>Schnetkamp, Paul P.M.</au><au>Green, Martin R.</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>SLC24A5 Encodes a trans-Golgi Network Protein with Potassium-dependent Sodium-Calcium Exchange Activity That Regulates Human Epidermal Melanogenesis</atitle><jtitle>The Journal of biological chemistry</jtitle><addtitle>J Biol Chem</addtitle><date>2008-02-29</date><risdate>2008</risdate><volume>283</volume><issue>9</issue><spage>5486</spage><epage>5495</epage><pages>5486-5495</pages><issn>0021-9258</issn><eissn>1083-351X</eissn><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 ∼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.</abstract><cop>United States</cop><pub>Elsevier Inc</pub><pmid>18166528</pmid><doi>10.1074/jbc.M707521200</doi><tpages>10</tpages><oa>free_for_read</oa></addata></record> |
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| source | MEDLINE; PMC (PubMed Central); EZB-FREE-00999 freely available EZB journals; Alma/SFX Local Collection |
| subjects | Animals Antiporters - genetics Antiporters - metabolism Calcium - metabolism Cell Line, Tumor Golgi Apparatus - genetics Golgi Apparatus - metabolism Humans Ion Transport - physiology Male Melanins - biosynthesis Melanins - genetics Melanocytes - cytology Melanocytes - metabolism Mice Pigmentation - physiology Polymorphism, Single Nucleotide Potassium - metabolism Sodium - metabolism Sodium-Calcium Exchanger - genetics Sodium-Calcium Exchanger - metabolism |
| title | SLC24A5 Encodes a trans-Golgi Network Protein with Potassium-dependent Sodium-Calcium Exchange Activity That Regulates Human Epidermal Melanogenesis |
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