Molecular basis and species specificity of high affinity binding of vasoactive intestinal polypeptide by the rat secretin receptor

Martin H. Holtmann, Elizabeth M. Hadac, Charles D. Ulrich, Laurence J Miller

Research output: Contribution to journalArticle

24 Citations (Scopus)

Abstract

The affinity and specificity of the binding interaction between ligands and their receptors are key for appropriate hormonal regulation of target tissues. However, it is now apparent that vasoactive intestinal polypeptide (VIP) binds to the rat secretin receptor with similar affinity to that for its natural ligand, secretin (Holtmann et al., 1995). In this report, we establish that this is not a characteristic of the human secretin receptor, and use rat-human secretin receptor chimeras, site mutants and truncated receptor constructs to establish the molecular basis for this unusual binding interaction. Of note, isolated N-terminal domains of the rat secretin and the VIP receptors are capable of high affinity binding of VIP. In the recently recognized secretin family of receptors, this domain has six conserved cysteine residues and disulfide bonds that are likely important to achieve the complex conformation critical for this binding. A single acidic residue (Asp98) present in the rat secretin receptor appears to be critical, because a site-mutant changing this to the polar, but uncharged residue present in that position in the human receptor (Asn) eliminates the high affinity binding of VIP. Of interest, a previously identified critical basic residue in VIP (Lys15) provides a candidate for charge-pairing with this residue, potentially aligning the peptide ligand in a nonproductive orientation within this receptor.

Original languageEnglish (US)
Pages (from-to)555-560
Number of pages6
JournalJournal of Pharmacology and Experimental Therapeutics
Volume279
Issue number2
StatePublished - Nov 1996

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Species Specificity
Vasoactive Intestinal Peptide
Secretin
Ligands
Disulfides
Cysteine
secretin receptor
Peptides

ASJC Scopus subject areas

  • Pharmacology

Cite this

Molecular basis and species specificity of high affinity binding of vasoactive intestinal polypeptide by the rat secretin receptor. / Holtmann, Martin H.; Hadac, Elizabeth M.; Ulrich, Charles D.; Miller, Laurence J.

In: Journal of Pharmacology and Experimental Therapeutics, Vol. 279, No. 2, 11.1996, p. 555-560.

Research output: Contribution to journalArticle

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