We previously showed that the metabotropic glutamate receptor 1alpha (mGluR1alpha) has a sensitivity to extracellular polyvalent cations such as Ca(2+) and Gd(3+) as well as glutamate. Here we show that mGluR1alpha-mediated responses to these ligands are modulated by the scaffold protein Homer. When HEK293 cells were transiently cotransfected with Homer 1c and mGluR1alpha, the maximum rate of rise and amplitude of glutamate-evoked [Ca(2+)](i) transients were increased and there was a rightward shift in the concentration-response relationship. The response of mGluR1alpha to abrupt increases in [Gd(3+)](o) was characteristic in that the concentration-response relationship was bell-shaped and Homer 1c broadened the effective range at both low and high concentrations. The effects of Homer 1a, which lacks clustering effect, differed qualitatively from those of Homer 1c. The effects of both Homer 1c and 1a on mGluR1alpha were decreased significantly in mGluR1alpha P1147E mutant which lacks the affinity to Homer, showing that the effects were mediated by binding to mGluR1alpha. Taken together, the binding of Homer 1c to mGluR1alpha was shown to cause not only an efficient link to Ca(2+)-store and a decrease in the surface expression, but also qualitative changes of the ligand-sensing function in a ligand type-specific manner.