Probing the immunological properties of the extracellular domains of the human beta(1)-adrenoceptor

The human beta(1)-adrenoceptor is an immune target for autoantibodies with functional activity in cardiovascular diseases. Different epitopes on the e xtracellular domains of the receptor are involved. To study the immunologic al and pharmacological properties of these epitopes, rabbits were immunized with peptides corresponding to a large domain in the N-terminal part of th e receptor and to its first and second extracellular loops. In contrast to the two other peptides, the first extracellular loop did not have immunogen ic properties but acted as a hapten. Antibodies affinity-purified with the three synthetic peptides were able to significantly immunoprecipitate the s olubilized receptor, confirming that they recognized the target receptor Wh ile antibodies against the N-terminal domain did not inhibit the binding of a radiolabelled antagonist to the receptor, those against the first and se cond extracellular loop showed non-competitive inhibition. Similarly, only the two latter antibodies exerted a specific agonist-like effect on the rec eptor, as assessed on neonatal rat. cardiomyocytes in culture. Our results are in accordance with those found for human anti-receptor autoantibodies w ith functional effects. We conclude that not all extracellular epitopes giv e rise to functional autoantibodies with potential physiopathological relev ance in cardiac diseases with an autoimmune component. (C) 1999 Academic Pr ess.