title: Metabotropic glutamate receptor 6 signaling enhances TRPM1 calcium channel function and increases melanin content in human melanocytes.
abstract: Mutations in TRPM1, a calcium channel expressed in retinal bipolar cells and epidermal melanocytes, cause complete congenital stationary night blindness with no discernible skin phenotype. In the retina, TRPM1 activity is negatively coupled to metabotropic glutamate receptor 6 (mGluR6) signaling through Gαo and TRPM1 mutations result in the loss of responsiveness of TRPM1 to mGluR6 signaling. Here, we show that human melanocytes express mGluR6, and treatment of melanocytes with L-AP4, a type III mGluR-selective agonist, enhances Ca(2+) uptake. Knockdown of TRPM1 or mGluR6 by shRNA abolished L-AP4-induced Ca(2+) influx and TRPM1 currents, showing that TRPM1 activity in melanocytes is positively coupled to mGluR6 signaling. Gαo protein is absent in melanocytes. However, forced expression of Gαo restored negative coupling of TRPM1 to mGluR6 signaling, but treatment with pertussis toxin, an inhibitor of Gi /Go proteins, did not affect basal or mGluR6-induced Ca(2+) uptake. Additionally, chronic stimulation of mGluR6 altered melanocyte morphology and increased melanin content. These data suggest differences in coupling of TRPM1 function to mGluR6 signaling explain different cellular responses to glutamate in the retina and the skin.
authors: Department of Dermatology, University of Wisconsin, School of Medicine and Public Health, Madison, WI, USA.
authors: Sulochana
authors: S
authors: Devi
authors: Yogananda
authors: Y
authors: Markandeya
authors: Nityanand
authors: N
authors: Maddodi
authors: Anuradha
authors: A
authors: Dhingra
authors: Noga
authors: N
authors: Vardi
authors: Ravi C
authors: RC
authors: Balijepalli
authors: Vijayasaradhi
authors: V
authors: Setaluri
mesh_terms: D002118:Calcium / Q000378:metabolism; D049109:Cell Proliferation / Q000187:drug effects; D000078404:Epidermal Cells; D019206:GTP-Binding Protein alpha Subunits, Gi-Go / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects; D018698:Glutamic Acid / Q000494:pharmacology; D006801:Humans; D007231:Infant, Newborn; D008297:Male; D008543:Melanins / Q000378:metabolism*; D008544:Melanocytes / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D018408:Patch-Clamp Techniques; D011422:Propionates / Q000494:pharmacology; D017470:Receptors, Glutamate / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D050053:TRPM Cation Channels / Q000378:metabolism*
chemical_list: C114785:2-amino-4-phosphono-propinate; C576075:GRM6 protein, human; D008543:Melanins; D011422:Propionates; D017470:Receptors, Glutamate; D050053:TRPM Cation Channels; C492059:TRPM1 protein, human; D018698:Glutamic Acid; D019206:GTP-Binding Protein alpha Subunits, Gi-Go; D002118:Calcium