Expression of the metabotropic glutamate receptor 5 (mGluR5) induces melanoma in transgenic mice

Abstract

Glutamate is the major excitatory neurotransmitter in the mammalian CNS and mediates fast synaptic transmission upon activation of glutamate-gated ion channels. In addition, glutamate modulates a variety of other synaptic responses and intracellular signaling by activating metabotropic glutamate receptors (mGluRs), which are G protein-coupled receptors. The mGluRs are also expressed in nonneuronal tissues and are implicated in a variety of normal biological functions as well as diseases. To study mGluR-activated calcium signaling in neurons, we generated mGluR5 transgenic animals using a Thy1 promoter to drive expression in the forebrain, and one founder unexpectedly developed melanoma. To directly investigate the role of mGluR5 in melanoma formation, we generated mGluR5 transgenic lines under a melanocyte-specific promoter, tyrosinase-related protein 1. A majority of the founders showed a severe phenotype with early onset. Hyperpigmentation of the pinnae and tail could be detected as early as 3-5 d after birth for most of the mGluR5 transgene-positive mice. There was 100% penetrance in the progeny from the tyrosinase-related protein 1-mGluR5 lines generated from founders that developed melanoma. Expression of mGluR5 was detected in melanoma samples by RT-PCR, immunoblotting, and immunohistochemistry. We evaluated the expression of several cancer-related proteins in tumor samples and observed a dramatic increase in the phosphorylation of ERK, implicating ERK as a downstream effector of mGluR5 signaling in tumors. Our findings show that mGluR5-mediated glutamatergic signaling can trigger melanoma in vivo. The aggressive growth and severe phenotype make these mouse lines unique and a potentially powerful tool for therapeutic studies.etabotropic glutamate receptors (mGluRs) are G proteincoupled receptors that are widely expressed in the brain and modulate many diverse signaling pathways. In the CNS, mGluR activation regulates ion channels, mediates slow excitatory and inhibitory responses, modulates neurotransmitter release, and regulates neuronal development and growth (1-3). In addition, various neurological disorders have been attributed to functional impairment of mGluRs in the CNS. The mGluRs (mGluR1-8) are classified into three groups on the basis of sequence identity and pharmacological properties. Group I mGluRs (mGluR1 and mGluR5) are G q -coupled receptors that activate PLCβ, resulting in intracellular Ca 2+ release and protein kinase C (PKC) activation (4).Although glutamate signaling is usually investigated in the context of CNS function, it clearly plays a role in nonneuronal cells as well. In particular, glutamate signaling has been described in astrocytes, cerebral endothelial cells, bone, and skin (5, 6). In bone cells, glutamate or NMDA application increases NMDA receptor currents (7). Similarly, mGluR5 expression has been observed in many types of cells other than neurons, including astrocytes, hepatocytes, melanocytes, osteoblast cells (8-11), fibroblast cells (12), and more recently, stem cells ...

Melanoma: from mutations to medicine

“…More recently, Choi et al (2011) showed that mice in which metabotropic glutamate receptor 5 (mGluR5) expression was driven by the Trp1 promoter also developed murine melanomas with high penetrance. Furthermore, mGluR5 expression could be documented in human melanomas and may provide an oncogenic signal through ERK (Choi et al 2011).…”

Activation of the Glutamate Receptor GRM1 Enhances Angiogenic Signaling to Drive Melanoma Progression

“…Recently, ectopic expression of the other group I metabotropic glutamate receptor, mGRM5, has been shown to also produce melanoma in a second transgenic model (13). …”

1H NMR metabolomics study of metastatic melanoma in C57BL/6J mouse spleen

“…A significant decreased level of glutamate in melanoma group suggests that the above mentioned pathways may have been profoundly disturbed. Glutamate signaling in cancer has stimulated extensive research interest recently and has shown great importance in human melanoma development (Namkoong et al 2007; Choi et al 2011; Stepulak et al 2005; Rzeski et al 2001). The blockade of glutamate receptors has been proposed as a promising novel therapy for treating melanoma (Song et al 2012).…”