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*

Date Ghrelin
1971 Motilin discovered using as bioassay the contractile effect of extracts of the duodenal mucosa from pigs on the canine stomach.
1976 In analogy with the release mechanism of other pituitary hormones, growth hormone releasing hormone (GHRH) is postulated to exist. Because enkephalins are weak releasers of growth hormone, it is proposed that GHRH may be structurally related to enkephalins.
1977 Analogues of enkephalins lacking opiate activity, but with enhanced potency to release growth hormone, are developed. They are referred to as growth hormone secretagogues (GHS).
1982 GHRH is isolated. Interest in GHSs declines.
1984 Synthesis of the GHS peptide GHRP-6, a potent releaser of growth hormone.
1984 It becomes clear that GHSs act via a receptor other than GHRH. Interest in GHS increases again.
1993 The first non-peptide GHS, L-692,429, is developed by Merck.
1995 Development of a more potent and orally active GHS, L-163,191 (MK-0677).
1996 Cloning of the GHS receptor (GHS-R) using expression cloning and MK-0677 as agonist.
1997 Two receptors related to GHS-R are cloned and named GPR38 and GPR39. Their ligand/agonist is unknown.14
1998 A patent is submitted for “motilin homologues”. Much later it will be realised that it is related to ghrelin.
1999, July Orphan receptor GPR38 is identified as the motilin receptor and renamed MTL-R1a. It is predicted that the natural ligand for GHS-R could be related to motilin.
1999, December Ghrelin discovered using the Ca response of a cell line expressing GHS-R and isolated from extracts of the rat stomach.
2000, August Ghrelin “re-discovered” as “motilin related peptide”.

*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.