The metabotropic glutamate receptors (mGluRs) are widely distributed in the brain and play important roles in synaptic plasticity. Here it is shown that some types of mGluRs are activated not only by glutamate but also by extracellular Ca2+ (Ca2+(o)). A single amino acid residue was found to determine the sensitivity of mGluRs to Ca2+(o). One of the receptors, mGluR1α, but not its point mutant with reduced sensitivity to Ca2+(o), caused morphological changes when transfected into mammalian cells. Thus, the sensing of Ca2+(o) by mGluRs may be important in cells under physiological condition.