We previously reported that a variant with extra amino acids exists in rat metabotropic glutamate receptor subtype 5 (mGluR5) and that the identical extra sequence also exists in the human mGluR5 cDNA. We herein report the complete sequence and the functional expression of two isoforms of mGluR5 from the human brain. The deduced amino acid sequence of the large extracellular domain is extremely well conserved between rat and human mGluR5 (98.6%) which suggests that the amino-terminal region of mGluR5 is functionally important. We show that the glutamate-evoked responses appear in Xenopus oocytes while expressing either of the two mGluR5 isoforms, which suggests that these two receptors from the human brain could activate phospholipase C and generate Ca(2+)-activated Cl- current. We compared some of the pharmacological profiles of these two isoforms, but no clear differences could be observed. Finally, we also examined the effect of exogenous G proteins on the mGluR5-evoked responses.