Identification of surrogate agonists for the human FPRL-1 receptor by autocrine selection in yeast

Christine Klein, Jeremy I. Paul, Karen Sauvé, Mary M. Schmidt, Loretta Arcangeli, John Ransom, Joshua Trueheart, John P. Manfredi, James R. Broach, Andrew J. Murphy

Research output: Contribution to journalArticle

128 Scopus citations

Abstract

We describe a procedure for isolating agonists for mammalian G protein- coupled receptors of unknown function. Human formyl peptide receptor like-1 (FPRL-1) receptor, originally identified as an orphan G protein-coupled receptor related to the formyl peptide receptor (FPR1), was expressed in Saccharomyces cells designed to couple receptor activation to histidine prototrophy. Selection for histidine prototrophs among transformants obtained with a plasmid-based library encoding random peptides identified six different agonists, each of whose production yielded autocrine stimulation of the receptor expressed in yeast. A synthetic version of each peptide promoted activation of FPRL-1 expressed in human embryonic kidney (HEK293) cells, and five of the peptides exhibited significant selectivity for activation of FPRL-1 relative to FPR1. One selective peptide was tested and found to mobilize calcium in isolated human neutrophils. This demonstrates that stimulation of FPRL-1 results in neutrophil activation and suggests that the receptor functions as a component of the inflammatory response. This autocrine selection protocol may be a generally applicable method for providing pharmacological tools to evaluate the physiological roles of the growing number of mammalian orphan G protein-coupled receptors.

Original languageEnglish (US)
Pages (from-to)1334-1337
Number of pages4
JournalNature Biotechnology
Volume16
Issue number13
DOIs
StatePublished - Dec 1 1998

All Science Journal Classification (ASJC) codes

  • Biotechnology
  • Bioengineering
  • Applied Microbiology and Biotechnology
  • Molecular Medicine
  • Biomedical Engineering

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