Secretin family (Class B) G protein-coupled receptors – from molecular to clinical perspectives

Abstract

Family B G protein-coupled receptors represent an important but under-researched group of receptors. This edition of the British Journal of Pharmacology considers the roles and pharmacology of a number of these receptors. Whilst common themes emerge, it is clear that more work is needed to understand the details of each receptor in order to properly exploit them therapeutically.

LINKED ARTICLES

This article is part of a themed section on Secretin Family (Class B) G Protein-Coupled Receptors. To view the other articles in this section visit http://dx.doi.org/10.1111/bph.2012.166.issue-1

GPCRs constitute a large family of cell surface proteins that respond to a diverse array of physiological stimuli to control cellular processes. GPCRs have been heavily exploited in the development of drugs but the therapeutic potential of these proteins is still relatively untapped. Most drugs that are active against GPCRs target the class/family A, or the rhodopsin family of GPCRs, which is the largest sub-grouping of these receptors. In recent years class/family B, or the secretin family of GPCRs, has attracted attention, particularly in the field of metabolic diseases. These GPCRs comprise 15 members and possess an extracellular amino terminal adaptation that accommodates the binding of peptides ranging from around 20 to 50 amino acids (Fredriksson et al., 2003).

Historically the pharmaceutical industry has struggled to develop agents that act on family B GPCRs. This is partly because the cognate receptor ligands do not serve as useful templates for the development of lead compounds. With more acceptance of peptidic therapeutics and the identification of some high affinity small molecules, this is now changing. There are now marketed therapies targeting glucagon-like peptide 1 (GLP-1), amylin, calcitonin and glucagon receptors and other promising drugs are at different stages of clinical development (Archbold et al., 2011).

There have been a series of very exciting advances in the field of family B GPCRs recently. Evidence for their involvement in pathological states continues to grow, affirming their importance as drug targets (Dunworth and Caron, 2009; Kadmiel et al., 2011). Allied to this there have been important advances in structural biology including the publication of several crystal structures of their N-termini, with or without bound ligands (Grace et al., 2004; Parthier et al., 2007; Pioszak and Xu, 2008; Runge et al., 2008; Grace et al., 2010; ter Haar et al., 2010; Pal et al., 2010; Kusano et al., 2011). This work increases our understanding of ligand binding and provides a useful platform for structure-based drug design.

Our knowledge of the structure of the transmembrane domains of family B GPCRs currently lags behind that of the family A, where we have an increasing repertoire of crystal structures of both ground-state and active receptors (Katritch et al., 2011). However, the existing family A crystal structures help our understanding of how family B GPCRs recognise G proteins and, following the lessons learnt from the family A crystalisations, several groups are currently attempting to crystalise a family B GPCR. When successful, this will represent a major step forward. Even without this, real progress is being made at producing novel antagonists and agonists, either orthosteric or allosteric, which act at family B GPCRs (Axelsen et al., 2012; de Graaf et al., 2011). There is also is an increasing awareness of the complexities of signalling mediated by these receptors and how they can be exploited by the production of biased agonists or modulated by association with other proteins such as receptor activity-modifying proteins, and by splicing (Hay et al., 2006; Karteris et al., 2010; Gesty-Palmer and Luttrell, 2011).

This themed issue of the British Journal of Pharmacology draws together a series of 11 review and two original research articles from a number of the leading groups in the field of family B GPCRs. This issue contains the first International Union of Pharmacology receptor review in collaboration with the British Journal of Pharmacology (Harmar et al., 2012). There are extensive discussions of the binding of peptides and non-peptide ligands to the secretin receptor (Miller et al., 2012), the GLP-1 receptor (Donnelly, 2012), VPAC receptors (Couvineau and Laburthe, 2012) and the calcitonin and calcitonin receptor-like receptors (Barwell et al., 2012). Two research papers explore the detailed pharmacology of peptide binding; the recognition of adrenomedullin by the adrenomedullin 1 receptor (Kuwasako et al., 2012) and the significance of species differences in the pharmacology of amylin receptors (Bailey et al., 2012). The way in which ligand binding can be modified by accessory proteins, and in particular the consequences of this for production of CGRP antagonists is reviewed by Moore and Salvatore (Moore and Salvatore, 2012). The unique way in which family B GPCRs may be activated is considered for the VPAC1 receptor (Langer, 2012). The diversity of signalling is explored by reference to the CRF1 receptor (Grammatopoulos, 2012) and the consequences of splicing on the function of family B GPCRs is considered by Furness and colleagues (Furness et al., 2012). Finally, the pathophysiological role of agents that act on family B receptors are considered in two reviews; one on adrenomedullin 2 (Hong et al., 2012) and the other on amylin and GLP-1 (Roth et al., 2012).

What is becoming clear is that one size does not fit all for GPCRs in general or for family B GPCRs. Although there are commonalities in their general mode of binding and activation, each family B GPCR has its own unique properties that lend it to its role in physiology and disease. By exploring these in detail, it is hoped that this collection of articles will stimulate further research into this family of GPCRs.

Conflict of interest

None.