Pharmacological Characterization and Investigation of N-Terminal Loop Amino Acids of Adrenomedullin 2 That Are Important for Receptor Activation.

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  • Additional Information
    • Source:
      Publisher: American Chemical Society Country of Publication: United States NLM ID: 0370623 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1520-4995 (Electronic) Linking ISSN: 00062960 NLM ISO Abbreviation: Biochemistry Subsets: MEDLINE
    • Publication Information:
      Original Publication: Washington, American Chemical Society.
    • Subject Terms:
      Adrenomedullin/*chemistry ; Adrenomedullin/*metabolism ; Receptors, Cell Surface/*metabolism; Amino Acid Sequence ; Animals ; COS Cells ; Chlorocebus aethiops ; Cyclic AMP/biosynthesis ; Humans
    • Abstract:
      Adrenomedullin 2 (AM2) is a peptide hormone with potent effects in the cardiovascular system. The N-terminal disulfide loop of AM2 is thought to be important for interacting with its receptors to initiate a signaling response. However, the relative contribution of each amino acid within this region is currently unknown. Thus, the region was investigated using an alanine scanning approach. Two AM2 peptides (AM2-47 and AM2-40) were directly compared at the CGRP, AM 1 , and AM 2 receptors in transfected Cos7 cells and found to have equivalent activity. Analogues of AM2-40 were then synthesized, substituting each individual amino acid within the disulfide loop with alanine. The ability of these analogues to stimulate a cAMP response was evaluated at the CGRP, AM 1 , and AM 2 receptors. AM2-40 L12A and T14A were less able to elicit cAMP responses through all tested receptors. In contrast, AM2-40 G13A was slightly more potent than the unmodified peptide at all tested receptors. Thus, it appears that residues within the disulfide loop region play differential roles in the ability of AM2 to stimulate cAMP production. The data provide the first structure-function investigation of AM2 agonism.
    • Accession Number:
      0 (Receptors, Cell Surface)
      148498-78-6 (Adrenomedullin)
      E0399OZS9N (Cyclic AMP)
    • Publication Date:
      Date Created: 20190723 Date Completed: 20200605 Latest Revision: 20200605
    • Publication Date:
      20231215
    • Accession Number:
      10.1021/acs.biochem.9b00571
    • Accession Number:
      31328503