Oral communication, CS7 / C27

Official XXIst International Pigment Cell Conference website - 21-24 Sept 2011, Bordeaux - France | updated: September 04 2011

A novel pathway for regulation of pigmentation by glutamate receptor mGluR6 through its action on TRPM1

Transient receptor potential, Melastatin 1 (TRPM1), a calcium channel expressed in epidermal melanocytes and retinal ON bipolar cells, has been shown to play a role, respectively, in melanin pigmentation and vision. However, TRPM1 mutations that cause congenital night blindness in humans seem to have no effect on skin pigmentation or skin photosensitivity, although TRPM1 mutations in Appaloosa horses are associated with both a coat color phenotype and night blindness. Recent studies have shown that in ON bipolar cells, activity of TRPM1 channel during activation of visual pathway is negatively coupled to glutamate and metabotropic glutamate receptor 6 (mGluR6) through Gα0. To understand the reasons for lack of skin pigmentation phenotype in individuals with TRPM1 mutations, we investigated whether mGluR6 and Gα0 are expressed in melanocytes and TRPM1 channel is functionally coupled to mGluR6. In cultured neonatal foreskin epidermal melanocytes, while mGluR6 protein is readily detected, Gα0 expression is undetectable by western blotting. Interestingly, treatment of melanocytes with glutamate receptor agonists L-glutamate or a group III specific agonist L-AP4 caused a dose dependent increase in calcium uptake, instead of a decrease, in ratiometric calcium imaging studies and an increase in inward current in whole-cell patch clamping studies. This increase is TRPM1-dependent since it was abolished by knockdown of TRPM1 by shRNA. These data indicate that TRPM1 activity is positively coupled to glutamate binding to its receptors. Treatment with glutamate or L-AP4 also caused a decrease in cell survival, increase in melanin content, a decrease in dendritic length and an increase in dendritic width. The effect of L-AP4, a mGluR6-selective agonist, was more pronounced than L-glutamate, supporting a role for mGluR6 in melanocyte biology. Knockdown of mGluR6 using shRNAs targeting both the 3’ and 5’ ends showed that the increased calcium uptake and inward current upon addition of glutamate agonists was mGluR6 dependent. These data show a functional link between glutamate receptor and TRPM1 in melanocytes and a novel regulatory pathway of calcium homeostasis involving glutamate receptors and TRPM1 implicating a role for neuronal glutamate receptor 6 in melanocyte biology and melanin pigmentation.

Advertisement from our sponsor: