Location and cell-type specific bias of metabotropic glutamate receptor, mGlu5, negative allosteric modulators

Emerging data indicate that G-protein coupled receptor (GPCR) signaling is not only determined by the agonist and a given receptor but also a variety of cell type-specific factors that can influence a receptor’s response. For example, the metabotropic glutamate receptor, mGlu5, which is implicated in a number of neuropsychiatric disorders such as depression, anxiety, and autism, also signals from inside the cell which leads to sustained Ca2+ mobilization versus rapid transient responses. Because mGlu5 is an important drug target, many negative allosteric modulators (NAMs) have been generated to modulate its activity. Here we show that NAMs such as AFQ056, AZD2066 and RG7090 elicit very different endpoints when tested in postnatal neuronal cultures expressing endogenous mGlu5 receptors. For example, AFQ056 fails to block mGlu5-mediated Ca2+ increases whereas RG7090 is very effective. These differences are not due to differential receptor levels since about the same number of mGlu5 receptors are present on ...