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Receptor-specific ligands distinguish natriuretic peptide receptors-A and -C in primate tissues

Authors
  • Sehl, Patricia1
  • Tom, Jeff Y.K.2
  • Oare, David2
  • Lowe, David G1
  • 1 Genentech Inc., Department of Cardiovascular Research, South San Francisco, CA, 94080, USA , South San Francisco
  • 2 Genentech Inc., Department of Bioorganic Chemistry, South San Francisco, CA, 94080, USA , South San Francisco
Type
Published Article
Journal
Molecular and Cellular Biochemistry
Publisher
Springer-Verlag
Publication Date
Jan 01, 1998
Volume
178
Issue
1-2
Pages
317–324
Identifiers
DOI: 10.1023/A:1006823732336
Source
Springer Nature
Keywords
License
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Abstract

Systemic clearance of atrial natriuretic peptide (ANP) is in part due to neutral endopeptidase (NEP) proteolysis and natriuretic peptide receptor-C (NPR-C) mediated endocytosis. Biological responses to ANP are primarily mediated by the membrane guanylyl cyclase-A/natriuretic peptide receptor-A (NPR-A). Analogs of ANP selective for NPR-A and/or resistant to NEP may have increased activity in those tissues where NPR-C and NEP are coexpressed with NPR-A. The analog of ANP termed vANP; [(R3D, G9T, R11S, M12L, G16R)ANP] is selective for human NPR-A with at least 10,000 fold reduction in affinity for human NPR-C. We report that rat NPR-A is insensitive to 10 nM vANP, demonstrating the limitations of this species in evaluating human therapeutic candidates. As an alternative approach we tested the binding and potency of receptor-selective and NEP-resistant ANP analogs in rhesus monkey tissues. Competition binding studies with a simplified version of vANP, sANP [(G9T, R11S, G16R)rANP], in rhesus monkey kidney and lung membrane preparations shows displacement of 125I-ANP from only a fraction of the total ANP receptor population, 30 and 85%, respectively. The remaining ANP binding sites can be occupied with the NPR-C selective ligand cANP(4-23). These data strongly suggest that only two classes of ANP receptor are present in these membrane preparations, NPR-A and NPR-C. The NEP resistant sANP derivative called sANP(TAPR) was 8 fold more potent (ED50 = 0.6 nM) than rANP (ED50 = SnM) in stimulating cGMP production in the lung membrane preparation. Our results demonstrate that the rhesus monkey natriuretic peptide receptors reflect the pharmacology of the human receptors, and that this species may be suitable to determine the role of NPR-C and NEP in peptide clearance and attenuating functional responses.

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