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.