CUTTING EDGE - HUMAN ANAPHYLATOXIN C4A IS A POTENT AGONIST OF THE GUINEA-PIG BUT NOT THE HUMAN C3A RECEPTOR

The interaction of human anaphylatoxin C4a with the guinea pig (gp) an d human (hu) C3a receptors (C3aR) was analyzed using human rC4a, which exhibited C4a-specific activity on guinea pig platelets. A gpC3aR of 475 residues with a large second extracellular loop and a peptide sequ ence similar to 60% identical to the huC3aR was isolated from a genomi c DNA library and found to be expressed in guinea pig heart, lung, and spleen. HEK-293 eel cotransfected with this clone, and a cDNA encodin g G alpha-16 specifically bound (K-d = 1.6 +/- 0.7 nM) and responded f unctionally to C3a with an intracellular calcium mobilization (ED50 = 0.18 +/- 0.02 nM), Human rC4a weakly bound to both the hu- and gpC3aR (IC50 > 1 mu M). However, only HEK-293 cells expressing the gpC3aR res ponded functionally to rC4a (ED50 = 8.7 +/- 0.52 nM), while cells expr essing the huC3aR did not (c less than or equal to 1 mu M) Thus, throu gh an interaction with the C3aR, huC4a may elicit anaphylatoxic effect s in guinea pigs but not in man.