Examination of Interspecies Differences in Renal and Skeletal Receptor Binding and Adenylate Cyclase Stimulation with Human Calcitonin*

Abstract

Target tissue responses were examined and compared in renal and skeletal tissues of two species, the rat and rabbit, employing human calcitonin [hCT-(l–32)] and the synthetic amino-terminal analogs [des-amino-Cys¹]hCT-(l–32), [N^a-acetyl-Cys¹]hCT-(l–32), and [NMet^1.7]hCT-(l–32) [NMet, normethionine (S-methylcysteine)] as probes of membrane binding and adenylate cyclase stimulation. Close concordance was observed within each species in the concentration of each peptide required for binding to specific sites on target tissue membranes and for stimulating adenylate cyclase. Each peptide was found to be more potent in rabbit than in rat tissue when assayed in the absence or presence of the synthetic guanyl nucleotide, guanyl-5′-ate imidodiphosphate; however the relative order of potency of the different peptides did not vary between species. Within each species the potency of each peptide was similar in both target tissues examined. The characteristics of membrane binding differed between the two species in that hormonal binding to rabbit renal membranes achieved equilibrium more slowly, dissociated less readily, and demonstrated a higher apparent affinity constant and a lower apparent binding capacity than binding to rat membranes. Under conditions of equivalent proteolytic activity, adenylate cyclase sensitivity to stimulation by hCT-(l–32) remained greater in rabbit than in rat renal membranes, indicating that the interspecies differences observed were not dependent on differential degradative processes. The results demonstrate that alterations in hormone responsiveness between species may occur at the earliest steps of the hormonetarget tissue interaction, perhaps due to modifications of the membrane-binding site, and suggest that such alterations may occur in parallel in at least several of the target tissues within each species. (Endocrinology106: 510, 1980)