Mammalian T cell death-associated gene 8 (TDAG8)s are activated by extracellular protons. In the present study, we examined whether the TDAG8 homologs of other species are activated by protons as they are in mammals. We found that Xenopus TDAG8 also stimulated cAMP response element (CRE)-driven promoter activities reflecting the activation of G s /cAMP signaling pathways when they are stimulated by protons. On the other hand, the activities of chicken and zebrafish TDAG8s are hardly affected by protons. Results using chimeric receptors of human and zebrafish TDAG8s indicate that the specificity of the proton-induced activation lies in the extracellular region. These results suggest that protons are not an evolutionarily conserved agonist of TDAG8.