Molecular Basis for Modulation of Metabotropic Glutamate Receptors and Their Drug Actions by Extracellular Ca2+
We demonstrated that ectopic expression of metabotropic glutamate receptor 1 (mGluR1/Grm1) in mouse melanocytes was sufficient to induce melanoma development in vivo with 100% penetrance. We also showed that about 60% of human melanoma biopsies and cell lines, but not benign nevi or normal human melanocytes expressed mGluR1, suggesting that GRM1 may be involved in melanomagenesis. mGluR1 is expressed primarily in neurons. In various non-neuronal cells, mGluR1 expression is regulated via binding of Neuron-Restrictive-Silencer-Factor (NRSF) to a Neuron-Restrictive-Silencer-Element (NRSE). Here, we report on the possibility that aberrant mGluR1 expression in melanoma is due to alterations in NRSF and/or NRSE. We show that in human melanocytes, binding of NRSF to NRSE in the GRM1 promoter region is necessary for the suppression of mGluR1 expression. We also show that inhibiting the expression of the transcription factor Sp1 or interference with its ability to bind DNA can result in increased mGluR1 expression perhaps via its function as a negative regulator. In addition, we also provide evidence that demethylation within the promoter region of GRM1 may also be a mechanism for the derepression of mGluR1 expression in melanocytes that progress to cell transformation and tumor formation.