Single C motif-1 (SCM-1)/lymphotactin is a member of the chemokine superfamily, but retains only the 2nd and 4th of the four cysteine residues conserved in other chemokines. In humans, there are two highly homologous SCM-1 genes encoding SCM-1alpha and SCM-1beta with two amino acid substitutions. To identify a specific receptor for SCM-1 proteins, we produced recombinant SCM-1alpha and SCM-1beta by the baculovirus expression system and tested them on murine L1.2 cells stably expressing eight known chemokine receptors and three orphan receptors. Both proteins specifically induced migration in cells expressing an orphan receptor, GPR5. The migration was chemotactic and suppressed by pertussis toxin, indicating coupling to a Galpha type of G protein. Both proteins also induced intracellular calcium mobilization in GPR5-expressing L1.2 cells with efficient mutual cross desensitization. SCM-1alpha bound specifically to GPR5-expressing L1.2 cells with a Kd of 10 nM. By Northern blot analysis, GPR5 mRNA of about 5 kilobases was detected strongly in placenta and weakly in spleen and thymus among various human tissues. Identification of a specific receptor for SCM-1 would facilitate our investigation on its biological function. Following the set rule for the chemokine receptor nomenclature, we propose to designate GPR5 as XCR1 from XC chemokine receptor-1.