TRPM1 forms ion channels associated with melanin content in melanocytes.
TRPM1 (melastatin), which encodes the founding member of the TRPM family of transient receptor potential (TRP) ion channels, was first identified by its reduced expression in a highly metastatic mouse melanoma cell line. Clinically, TRPM1 is used as a predictor of melanoma progression in humans because of its reduced abundance in more aggressive forms of melanoma. Although TRPM1 is found primarily in melanin-producing cells and has the molecular architecture of an ion channel, its function is unknown. Here we describe an endogenous current in primary human neonatal epidermal melanocytes and mouse melanoma cells that was abrogated by expression of microRNA directed against TRPM1. Messenger RNA analysis showed that at least five human ion channel-forming isoforms of TRPM1 could be present in melanocytes, melanoma, brain, and retina. Two of these isoforms are encoded by highly conserved splice variants that are generated by previously uncharacterized exons. Expression of these two splice variants in human melanoma cells generated an ionic current similar to endogenous TRPM1 current. In melanoma cells, TRPM1 is prevalent in highly dynamic intracellular vesicular structures. Plasma membrane TRPM1 currents are small, raising the possibility that their primary function is intracellular, or restricted to specific regions of the plasma membrane. In neonatal human epidermal melanocytes, TRPM1 expression correlates with melanin content. We propose that TRPM1 is an ion channel whose function is critical to normal melanocyte pigmentation and is thus a potential target for pigmentation disorders.
Howard Hughes Medical Institute, Department of Cardiology, Children's Hospital Boston, Harvard Medical School, Boston, MA 02115, USA. Elena_Oancea@Brown.edu
Elena
E
Oancea
Joris
J
Vriens
Sebastian
S
Brauchi
Janice
J
Jun
Igor
I
Splawski
David E
DE
Clapham
D017398:Alternative Splicing; D000818:Animals; D015153:Blotting, Western; D001921:Brain / Q000378:metabolism; D002460:Cell Line; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D020869:Gene Expression Profiling; D049452:Green Fluorescent Proteins / Q000235:genetics / Q000378:metabolism; D006801:Humans; D007231:Infant, Newborn; D008543:Melanins / Q000378:metabolism*; D008544:Melanocytes / Q000166:cytology / Q000378:metabolism* / Q000502:physiology; D008545:Melanoma / Q000235:genetics / Q000473:pathology / Q000503:physiopathology; D008564:Membrane Potentials / Q000502:physiology; D051379:Mice; D035683:MicroRNAs / Q000235:genetics; D018408:Patch-Clamp Techniques; D020033:Protein Isoforms / Q000235:genetics / Q000378:metabolism / Q000502:physiology; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism; D012160:Retina / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D050053:TRPM Cation Channels / Q000235:genetics / Q000378:metabolism* / Q000502:physiology; D014162:Transfection
D008543:Melanins; D035683:MicroRNAs; D020033:Protein Isoforms; D011993:Recombinant Fusion Proteins; D050053:TRPM Cation Channels; C492059:TRPM1 protein, human; C116297:Trpm1 protein, mouse; D049452:Green Fluorescent Proteins