Metabotropic glutamate receptors (mGlus) are a group of Family C Seven Transmembrane Spanning Receptors (7TMRs) that play important roles in modulating signaling transduction, particularly within the central nervous system. mGlu4 belongs to a subfamily of mGlus that is predominantly coupled to Gi/o G proteins. We now report that the ubiquitous autacoid and neuromodulator, histamine, induces substantial glutamate-activated calcium mobilization in mGlu4-expressing cells, an effect which is observed in the absence of co-expressed chimeric G proteins. This strong induction of calcium signaling downstream of glutamate activation of mGlu4 depends upon the presence of H1 histamine receptors. Interestingly, the potentiating effect of histamine activation does not extend to other mGlu4-mediated signaling events downstream of Gi/o G proteins, such as cAMP inhibition, suggesting that the presence of Gq coupled receptors such as H1 may bias normal mGlu4-mediated Gi/o signaling events. When the activity induced by small molecule positive allosteric modulators of mGlu4 is assessed, the potentiated signaling of mGlu4 is further biased by histamine toward calcium-dependent pathways. These results suggest that Gi/o-coupled mGlus may induce substantial, and potentially unexpected, calcium-mediated signaling events if stimulation occurs concomitantly with activation of Gq receptors. Additionally, our results suggest that signaling induced by small molecule positive allosteric modulators may be substantially biased when Gq receptors are co-activated.
This article is part of a Special Issue entitled ‘Metabotropic Glutamate Receptors’.