D-amino acid-substituted atrial natriuretic peptide analogs reveal novel receptor recognition requirements.
The introduction of D-amino acid residues into peptide hormones has been traditionally utilized in structure-activity studies to probe the conformational requirements of ligand-receptor interactions. A study was undertaken to examine the effect of D-amino acid substitutions into the atrial natriuretic peptide molecule on interactions with distinct subpopulations of specific membrane-associated receptors of bovine aortic smooth muscle cells. Competitive binding analysis revealed that each of 15 synthetic D-amino acid-substituted analogs showed comparable affinities for C-ANP receptors, a class of specific receptors which have been proposed to mediate the sequestration and metabolic clearance of ANP. The relative affinities of all 15 analogs did not differ more than 10-fold. In contrast, the interaction of the ANP analogs with a second receptor pool (B-ANP receptors), which is coupled to the stimulation of particulate guanylate cyclase, varied over a 1000-fold range of potency consistent with expectations for a receptor that displays rigorous conformational specificity. The indiscriminant selectivity of C-ANP receptors for D-amino acid-substituted ANP analogs is unprecedented for hormone receptors involved in biological signal transduction. These results, when coupled with the inability to correlate any direct in vitro biological effect associated with C-ANP receptor occupancy supports the hypothesis that the C-ANP receptor protein is a novel transport protein involved in the metabolic clearance of ANP.
Scarborough
R M
RM
California Biotechnology Inc., Mountain View 94043.
McEnroe
G A
GA
Arfsten
A
A
Kang
L L
LL
Schwartz
K
K
Lewicki
J A
JA
D000345:Affinity Labels / Q000378:metabolism; D000596:Amino Acids / Q000032:analysis*; D000818:Animals; D009320:Atrial Natriuretic Factor / Q000032:analysis*; D001665:Binding Sites; D001667:Binding, Competitive; D002417:Cattle; D006152:Cyclic GMP / Q000494:pharmacology; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000378:metabolism; D013329:Structure-Activity Relationship
D000345:Affinity Labels; D000596:Amino Acids; D009320:Atrial Natriuretic Factor; D006152:Cyclic GMP