Ghrelin: Back to the basics – Part 1

Posted 8/10/2018

As peptide medicine continue to dominated by products such as GHRP2, GHRP6, and Ipamorelin. It might be helpful to have context regarding Ghrelin, the endogenous signaler which the Growth Hormone Secretagogues we designed to mimic.

Although most think of Ghrelin as the hunger hormone, it was actually named for its interaction with the Ghrowth Hormone Secretagogue receptor (GHS).  Ghrelin, from “ghre” the Indo-European root for “to grow and “relin” a suffix used for releasing substances, wasn’t discovered until 1999.

Before the endogenous ligand was discovered, they had actually already synthesized many exogenous signaling molecules for the GHS receptor.  Hexarelin and “growth hormone releasing peptide-6” (GHRP-6) were the first to be synthesized.  Based of enkephalins, these were devoid of opioid activity, but potent releasers of growth hormone from the pituitary. They became known as growth hormone secretagogues (GHSs).

When growth hormone releasing hormone (GHRH) was isolated in 1982, interest in GHSs declined until it was realized in 1984 that GHSs and GHRH act via different receptors. This stimulated the pharmaceutical industry to develop non-peptide GHSs and one of them, MK-0677 (aka Ibutamorelin), enabled the MSD group led by R Smith to clone the GHS receptor (GHS-R) in 1996.

Unbeknownst to many who prescribe it currently, all these peptides which are still used medically were created before ghrelin itself was actual characterized.  Eventual, Kojima and colleagues discovered  it and found some surprising results regarding its location and expression.

To their surprise, the largest source of ghrelin was in the stomach, and in particular it was isolated from the gastric mucosa.

The discovery of ghrelin was also important because it was previously unlike any receptor that had been categorized. It’s receptor and that of its structurally related peptide Motilin are both are classical G protein coupled seven transmembrane domain receptors but they are unrelated to other subfamilies of G protein coupled receptors (GPCRs) and therefore form a new receptor subfamily.

Its structural features are also striking. For GHS-R, the activation domain involves transmembrane domain 2 (TM2) and TM3, and this domain has been remarkably conserved over more than 400 million years of evolution.

Since then, we have begun to find out a lot about Ghrelin and its actions.  Ultimately, Ghrelin is a 28-aa Ser3 acylated peptide, and its functionally relevant endogenous receptor is growth hormone secretagogue receptor (GHS-R). Ghrelin is a key regulator of nutrient sensing, meal initiation, and appetite. Apart from its orexigenic effect, research in the last decade has shown that ghrelin has regulatory roles in in many organs and systems . Ghrelin signaling has increasingly been recognized as a key regulator of obesity, insulin resistance and diabetes; intriguingly, many of these regulatory functions appear to be independent of ghrelin’s effect on food intake.

We will continue to post more on Ghrelin, its receptor (GHS-R), and how this all plays a role in how we use the GHRPs in part 2.

Table 1

Milestones in the discovery of ghrelin*

*Data until 1996 compiled from the reviews of Bowers² and Casanueva and Dieguez.¹⁵ Items related to motilin are in italics. The discovery date of motilin has also been added.