Somatic mutation of GRIN2A in malignant melanoma results in loss of tumor suppressor activity via aberrant NMDAR complex formation.

The ionotropic glutamate receptors( N -methyl-D-aspartate receptors (NMDARs)) are composed of large complexes of multi- protein subunitscreating ion channels in the cell plasma membranes that allow for influx or efflux of mono- or divalent cations (e.g., Ca 2+ ) important for synaptic transmissions, cellular migration, and survival. Recently, we discovered the high prevalence of somatic mutations within one of the ionotropic glutamate receptors, GRIN2A, in malignant melanoma. Functional characterization of a subset of GRIN2Amutants demonstrated a loss of NMDAR complex formation between GRIN1and GRIN2A, increased anchorage-independent growth in soft agar, and increased migration. Somatic mutation of GRIN2Aresults in a dominant negative effect inhibiting the tumor-suppressive phenotype of wild-type (WT) GRIN2Ain melanoma. Depletion of endogenous GRIN2Ain melanoma cells expressing WT GRIN2Aresulted in increased proliferation compared with control. In contrast, short-hairpin RNA depletion of GRIN2Ain mutant cell lines slightly reduced proliferation. Our data show that somatic mutation of GRIN2Aresults in increased survival, and we demonstrate the functional importance of GRIN2Amutations in melanoma and the significance that ionotropic glutamate receptorsignaling has in malignant melanoma.