Cross-chimeric analysis of selectivity of secretin and VPAC1 receptor activation

C. G. Park, S. C. Ganguli, D. I. Pinon, E. M. Hadac, L. J. Miller

Research output: Contribution to journalArticle

20 Scopus citations

Abstract

Agonist action at receptors is highly specific, affected by the structure of both ligand and receptor. Chimeric constructs of structurally related receptors and/or ligands that have biological differences provide an opportunity to correlate a specific structural domain with function. In this work, we have used a cross-chimeric approach to explore the structural basis for rat secretin and vasoactive intestinal polypeptide action at their closely related secretin and VPAC1 receptors, belonging to class II of the G protein-coupled receptor superfamily. Multiple domains of both ligands and receptors contributed toward their selectivity, with differing combinations of such domains able to support high-potency interactions. The amino-terminal 15 residues of secretin were most critical for potent stimulation of secretin receptors, whereas either the amino- or carboxyl-terminal halves of vasoactive intestinal polypeptide, when complemented by Lys15, provided potent stimulation of the VPAC1 receptor. The amino terminus of the VPAC1 receptor was most critical for potent response to vasoactive intestinal polypeptide, whereas the amino terminus of the secretin receptor was important, but not adequate, requiring the complementation of an extracellular loop domain for potent response to secretin. Differences in the distribution of these determinants within these receptors provided an opportunity to produce a more 'universal' receptor that contained the first extracellular loop of the secretin receptor and the remainder of the VPAC1 receptor. This cross-chimeric approach should be applied to other members of this receptor family to test the emerging themes and to expand these insights as broadly as possible.

Original languageEnglish (US)
Pages (from-to)682-688
Number of pages7
JournalJournal of Pharmacology and Experimental Therapeutics
Volume295
Issue number2
StatePublished - Jan 1 2000

ASJC Scopus subject areas

  • Molecular Medicine
  • Pharmacology

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