Metabotropic glutamate receptor 6 signaling enhances TRPM 1 calcium channel function and increases melanin content in human melanocytes
Open accessAbstract
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.
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Glutamate signaling genes are widely expressed in tissues beyond the CNS, including osteoblasts, osteoclasts, melanocytes, and chondrocytes.
“Glutamate signaling genes are also widely expressed in tissues beyond the CNS, including osteoblasts, osteoclasts, melanocytes, and chondrocytes (Wang et al., 2005;Hoogduijn et al., 2006;Devi et al., 2013;Julio-Pieper et al., 2011;Matta, 2013).”
From Glutamate receptors in domestication and modern human evolution (2020) · cites this paper as Devi et al., 2013
Some evidence for direct effects of glutamate signaling derives from the fact that glutamate receptor, transporter, and other signaling genes identified in different domestication studies are expressed in melanocytes, osteoblasts, osteoclasts, chondrocytes, and other tissues beyond the CNS.
“Some evidence for this derives from the fact that glutamate receptor, transporter, and other signaling genes identified in different domestication studies are expressed in melanocytes, osteoblasts, osteoclasts, chondrocytes, and other tissues beyond the CNS (Wang et al., 2005;Hoogduijn et al., 2006;Devi et al., 2013;Julio-Pieper et al., 2011;Matta, 2013).”
From Glutamate receptors in domestication and modern human evolution (2020) · cites this paper as Devi et al., 2013
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- Authors
- Devi, S., Markandeya, Y., Maddodi, N., Dhingra, A., Vardi, N., Balijepalli, R. C., & Setaluri, V.
- Affiliations
- University of Wisconsin–Madison (US)
- University of Pennsylvania (US)
- Corresponding author
- Setaluri, Vijayasaradhi
- Venue
- Pigment Cell & Melanoma Research
- Publisher
- Wiley
- Published
- 2013-03-27
- Volume
- 26
- Issue
- 3
- Pages
- 348-356
- ISSN
- 1755-1471 (ISSN-L)
- 1755-148X
- PMC
- PMC3682403
- OpenAlex
- W1969402512
- Cited by
- 45
- References
- 43
- Citations by year
- 2026: 5 · 2025: 3 · 2023: 3 · 2022: 4 · 2021: 2 · 2020: 3 · 2019: 5 · 2018: 4 · 2017: 3 · 2016: 3 · 2015: 2 · 2014: 4 · 2013: 4
- FWCI
- 3.60
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Pigment Cell & Melanoma Research (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- Dermatology Foundation
- National Institutes of Health
- National Eye Institute (R01EY011105, NEI EY11105)
- National Cancer Institute (P30CA014520)
- National Institute of Arthritis and Musculoskeletal and Skin Diseases (AR056087, R01AR056087)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Physiology › Calcium signaling and nucleotide metabolism
- Life Sciences › Neuroscience › Sensory Systems › Ion Channels and Receptors
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › melanin and skin pigmentation
- Keywords
- mGluR6, TRPM1, calcium channels, melanocytes, melanin content, Gαo, L-AP4, congenital stationary night blindness, calcium influx, melanocyte morphology, Gi/Go proteins, retinal bipolar cells, skin pigmentation
- MeSH terms
- Epidermal Cells, Calcium, Gene Expression Regulation, Humans, Infant, Newborn, Male, Melanins, Melanocytes, Propionates, Signal Transduction, Receptors, Glutamate, Patch-Clamp Techniques, Glutamic Acid, GTP-Binding Protein alpha Subunits, Gi-Go, Cell Proliferation, TRPM Cation Channels
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