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Molecular Pharmacology Fast Forward
First published on April 21, 2006; DOI: 10.1124/mol.106.025932

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Received for publication April 21, 2006.
Revised April 20, 2006.
Accepted for publication April 21, 2006.

Class B GPCRs: A hidden agonist within ? (Relates to article by Dong, et al. FastForward 10 March 2006)

Martin Beinborn 1*

1 Tufts-New England Medical Center

* Address correspondence to: E-mail: mbeinborn{at}tufts-nemc.org

Abstract

Class B G protein-coupled receptors (GPCRs) regulate a wide range of endocrine and neuroendocrine functions and are endogenously stimulated by moderately large peptide hormones. Current evidence suggests that the carboxy-termini of cognate peptides bind to the amino-terminus of their GPCRs, and that the peptides' amino terminal segments then dock to the heptahelical receptor portion to induce signaling. In the current issue of Molecular Pharmacology, Dong et al. propose an alternative model of ligand-induced class B GPCR activation. Based primarily on studies with the secretin receptor, a prototype class B family member, they provide evidence that the endogenous peptide hormone does not function as an activator per se. Instead, this hormone (secretin) exposes a hidden, built-in agonist epitope that is present within the amino-terminus of its target GPCR. Isolated oligopeptide fragments containing this epitope act as full agonists on the secretin receptor despite lacking amino acid homology with the secretin hormone. These non-conventional agonists can be minimized to tripeptide molecules and still maintain biological activity. The study to be discussed introduces a novel paradigm of class B GPCR function, and may facilitate the elusive goal of finding small molecule agonist drugs for this therapeutically attractive group of receptors.


Key words: Neuropeptides, Structure-activity relationships and modeling, Func. analysis receptor/ion channel mutants, Peptide hormones


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