Ghrelin axis genes, peptides and receptors: Recent findings and future challenges

Abstract

The ghrelin axis consists of the gene products of the ghrelin gene (GHRL), and their receptors, including the classical ghrelin receptor GHSR. While it is well-known that the ghrelin gene encodes the 28 amino acid ghrelin peptide hormone, it is now also clear that the locus encodes a range of other bioactive molecules, including novel peptides and non-coding RNAs. For many of these molecules, the physiological functions and cognate receptor(s) remain to be determined. Emerging research techniques, including proteogenomics, are likely to reveal further ghrelin axis-derived molecules. Studies of the role of ghrelin axis genes, peptides and receptors, therefore, promises to be a fruitful area of basic and clinical research in years to come.

Introduction

Howard et al. (1996) described the growth hormone secretagogue receptor (GHSR), which is expressed in the pituitary and hypothalamus and mediates the growth hormone (GH)-releasing activities of synthetic peptide secretagogues and cyclic analogues. GHSR was shown to be a classical, 7-transmembrane domain, G protein-coupled orphan receptor, and its natural ligand was not known. Three years later, Kojima et al. (1999) isolated the natural GHSR ligand, ghrelin, from rat stomach. The ghrelin axis has now been described in a range of vertebrate species from teleost fish to humans (Kaiya et al., 2008). Although ghrelin was initially discovered as an endogenous GH-releasing peptide, it soon became apparent that ghrelin has a wide range of different functions. Ghrelin is the most potent circulating orexigen, and plasma levels are elevated prior to meals and stimulate feeding (Wren et al., 2001). It also has roles in the regulation of metabolism, insulin and glucose balance, the immune system, cardiovascular system and has roles in sleep and memory.

Ghrelin is a 28 amino acid peptide, which is post-translationally cleaved by furin-like proteases from a larger (117 amino acid) preproghrelin protein. We have previously hypothesised that the ghrelin gene encodes a wide range of peptides, termed crypteins (meaning to hide in Greek) (Seim et al., 2009), and recent evidence supports this hypothesis. These hidden peptides, which are derived by alternative transcriptional splicing, proteolytic cleavage of larger precursor peptides and/or by other post-translational modifications, may have novel or altered functions compared to the wild-type ghrelin peptide. Although the human ghrelin gene was originally reported to consist of just four coding exons, recent evidence demonstrates that the human ghrelin gene locus is remarkably more complex in terms of transcriptional output, and includes a large number of transcripts transcribed from both sense and antisense DNA strands (Seim et al., 2007, Seim et al., 2008).

There also appears to be considerable diversity in the ghrelin receptor. Alternative splicing of the GHSR gene generates the full-length transcript that encodes the active GHSR 1a and a truncated GHSR 1b isoform, the latter exhibits no calcium signalling in response to ghrelin treatment (Feighner et al., 1998, Howard et al., 1996), but may downregulate GHSR1a expression, acting as a dominant-negative mutant (Leung et al., 2007). There is also strong evidence for an unidentified, alternative ghrelin receptor(s) that could mediate some of the effects of ghrelin and its non-acylated form, desacyl ghrelin (Baldanzi et al., 2002, Bedendi et al., 2003, Broglio et al., 2004, Cassoni et al., 2001, Cassoni et al., 2004, Filigheddu et al., 2007, Gauna et al., 2005, Gauna et al., 2006, Kleinz et al., 2006, Martini et al., 2006, Muccioli et al., 2004, Sato et al., 2006, Thielemans et al., 2007, Thompson et al., 2004, Toshinai et al., 2006, Tsubota et al., 2005).

In this review, we will highlight what is known about human ghrelin axis-derived molecules, ghrelin receptors and RNA transcripts, many of which may play important roles in health and disease.