Growth Hormone Secretagogue Receptor Research: GHS-R1a and the Ghrelin Story

GHS-R1a was found because of synthetic peptides; its hormone came afterwards. Structure, constitutive activity, and what the research reports.

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Most receptors are discovered by chasing a hormone. This one was discovered by chasing a drug.

In 1984 a synthetic hexapeptide was reported to act on the pituitary to release growth hormone by a route that the growth hormone-releasing hormone receptor could not account for. Twelve years later the receptor responsible was identified. Three years after that, its endogenous ligand was found. The sequence — compound, then receptor, then hormone — is the reverse of the usual one, and it shapes the whole literature that follows.

This article sets out what the growth hormone secretagogue receptor is, what is established about its signalling and structure, and what the published research at each level reports. It describes research and contains no guidance of any kind on handling any material.

What the receptor is

The growth hormone secretagogue receptor type 1a, GHS-R1a, is a class A — rhodopsin-like — G protein-coupled receptor. That places it in a different structural family from the GHRH, GLP-1, GIP and glucagon receptors discussed elsewhere in this library, which are class B1. It was identified in 1996 in pituitary and hypothalamus as the receptor that functions in growth hormone release in response to the synthetic secretagogues [6].

Its endogenous ligand is ghrelin, identified in 1999 as an acylated peptide from the stomach [14]. The acylation is not incidental: ghrelin carries an octanoyl group on a serine residue, and that modification is required for activity at the receptor. Ghrelin is one of the few peptide hormones whose natural form is post-translationally lipidated as a condition of function.

Two consequences of the discovery order are worth naming, because they run through everything below.

The synthetic ligands are not analogues of the hormone. GHRP-6, GHRP-2 and ipamorelin have no sequence relationship to ghrelin. They were found by structure-activity work on peptides that did something interesting, before anyone knew what the natural ligand was [18].

The receptor's name records the drugs, not the hormone. "Growth hormone secretagogue receptor" is a pharmacological name. The functional literature increasingly calls it the ghrelin receptor, and the two names denote the same protein.

How the receptor was found

Animal research

The founding observation is a rat experiment. A new synthetic hexapeptide, later called GHRP-6, was reported in 1984 to act on the pituitary to release growth hormone specifically: concentrations rose within two minutes of intravenous administration, peaked at 10 to 20 minutes, and had usually returned to baseline by two hours. Somatostatin-14 and somatostatin-28 both inhibited the response, with somatostatin-28 the more active [1].

The growth hormone-releasing peptide family grew from there, and by the mid-1990s its clinical and basic aspects were substantial enough to review as a family [7]. The development of the class, including the structure-activity work that produced its later members, has been set out in review [18].

The decisive selectivity result came in 1998. Ipamorelin, a pentapeptide, was characterised in swine as releasing growth hormone without measurable release of ACTH or cortisol — which the earlier hexapeptides did not manage — and pharmacological profiling with GHRP and GHRH antagonists placed its action at the secretagogue receptor rather than at the GHRH receptor [9]. That experiment is what separates the two receptor systems pharmacologically.

The receptor's role extends beyond the pituitary. Central administration of ghrelin and of growth hormone secretagogues was shown to induce feeding and activate brain regions associated with food intake in rodents [16] — the finding that connected this receptor to a second physiology entirely. Rodent work on GHRP-6 specifically reported that its effects on body mass and fat accrual depend on the pubertal stage and the sex of the animal, an unusually explicit statement of how conditional such findings are [22].

Other rodent work has examined secretagogues at this receptor in longitudinal bone growth [12], in glucocorticoid-induced reduction of bone formation in adult rats [15], in models of postoperative gastrointestinal dysmotility [21, 24], and more recently in a cisplatin model comparing two GHS-R1a agonists [28].

Findings described in this section were observed in animals. Nothing in them establishes anything about humans.

What is established about signalling and structure

In vitro research

Three properties of this receptor are established at the molecular level and are unusual enough to be worth stating individually.

It has high constitutive activity. The receptor signals substantially in the absence of any ligand. That was demonstrated in 2003, along with the identification of a potent inverse agonist — a compound that reduces signalling below the unliganded baseline rather than merely failing to raise it [17]. The practical consequence is that a complete account of pharmacology at this receptor has to address basal tone, not only agonist occupancy: two agonists with identical potency could differ in how they interact with a receptor that is already signalling.

Its signalling can be biased. Agonism, antagonism and inverse agonism bias at the receptor were characterised in 2015, showing that different ligands can favour different downstream routes rather than simply producing more or less of one output [26].

Its structure has been solved in an antagonist-bound state. A 2020 structure of the antagonist-bound receptor provided a structural account of how ghrelin might be recognised, including how the acyl chain is accommodated [27].

The contrast with the GHRH receptor is instructive and is the reason these two systems are so often confused. The GHRH receptor is a class B1 receptor cloned from human anterior pituitary in 1993, with a conventional relationship to its natural peptide ligand [2]. GHS-R1a is a class A receptor with a lipidated natural ligand, high basal activity and biased signalling. They converge on the same pituitary cell and are otherwise very different proteins.

These are observations in cell-based assays and structural biology. They describe molecular behaviour and establish nothing about animals or people.

What the human research at this receptor reports

Human clinical research

Results from pharmaceutical clinical trials describe the investigational material and populations used in those studies and should not be interpreted as establishing the effects of research-grade materials offered for laboratory use.

The human literature at this receptor is dominated by diagnostic and mechanistic pharmacology rather than by therapeutic trials, and that shape is the most important thing about it.

Provocative testing

The largest body of human work uses a secretagogue at this receptor as a provocative agent to assess pituitary reserve.

In 77 healthy participants and 58 patients with a peak growth hormone below 3 µg/l on the insulin tolerance test, a single 100 µg intravenous administration of GHRP-2 produced a serum growth hormone peak within 60 minutes in every participant. Peak concentrations were significantly lower in patients (1.36 ± 2.60 µg/l) than in the healthy group (84.6 ± 60.9 µg/l), p < 0.001, with no difference between hypothalamic and pituitary disease; responses were unaffected by sex, slightly lower with age and adiposity, and reproducible on repeat testing. The sensitivity–specificity crossing point fell between 15 and 20 µg/l [19].

In 56 children with growth disorders, a 2 µg/kg intravenous administration correlated favourably with the insulin tolerance test (p < 0.0001), with peak concentrations significantly lower in children with growth hormone deficiency (median 3.39 µg/l) than without (25.10 µg/l), and the same 15 µg/l crossing point [23]. Earlier work in 24 children compared responses to a secretagogue and to GHRH in the same participants and reported them similar, with a synergistic response when both were administered together [3]; diagnostic use of intravenous and intranasal administration in children of short stature was reported in the same period [4]. A separate study compared the arginine test and the GHRP-2 test against the insulin tolerance test as reference [25].

The ACTH response — which distinguishes the hexapeptides from ipamorelin — has itself been examined diagnostically in patients with hypopituitarism [20], and continuous 24-hour infusion in women has been used to characterise activation of the growth hormone axis [11].

Limitations. These are validation studies of diagnostic thresholds, not studies of any clinical outcome. They establish that a test discriminates in the population enrolled, against a reference test whose own thresholds are debated.

Distinguishing the two receptor systems in the same people

The most mechanistically informative human studies administer a secretagogue and GHRH to the same participants, which compares two receptor routes rather than two compounds.

In 21 patients with type 2 diabetes split by body-mass index, plus 8 normal-weight controls, each given GHRP-6 90 µg intravenously, GHRH 100 µg intravenously, and both together on separate occasions: growth hormone responses to GHRP-6 did not differ across the three groups — peaks of 50.95 ± 11.55, 51.96 ± 7.71 and 70.07 ± 15.59 mU/L, p > 0.05 — while the response to GHRH was reduced in the overweight diabetic group relative to the normal-weight diabetic group (peak 8.25 ± 1.90 against 22.19 ± 8.81, p < 0.05) [10].

Comparable designs have been applied in hyperthyroidism [5] and in patients with microprolactinoma and macroprolactinoma before and after bromocriptine therapy [8].

Limitations. Small, single-centre, condition-specific pharmacological studies with hormone concentrations as endpoints. None measured a clinical outcome, and none assessed repeated administration over time.

Therapeutic programmes

There are very few. Ipamorelin's published human record is a single pharmacokinetic study in healthy male volunteers — pharmacokinetics proportional to the amount administered, terminal half-life about two hours, clearance 0.078 L/h/kg, steady-state volume of distribution 0.22 L/kg, with growth hormone release as a single episode peaking at approximately 0.67 hours [13] — plus two registered phase 2 trials in postoperative gastrointestinal function whose results were not published in the peer-reviewed literature [29, 30].

Regulatory position. GHRP-2, under the international non-proprietary name pralmorelin, is approved in Japan as a diagnostic agent for provocative testing of growth hormone secretion. No compound acting at this receptor is approved in the United States for any indication, diagnostic or therapeutic.

What remains unsettled

Whether the constitutive activity matters clinically. The receptor's high basal signalling and the existence of inverse agonists are established in vitro [17], and no clinical programme has been built around modulating basal tone rather than adding agonist.

Whether selectivity translates. Ipamorelin's selectivity for growth hormone release over ACTH and cortisol was demonstrated in swine [9]. Its published human record is one pharmacokinetic study, and the two phase 2 trials that might have addressed it clinically did not report [13, 30].

What the second physiology implies. The connection between this receptor and the regulation of food intake was established in rodents [16], and the human literature at this receptor is almost entirely about growth hormone.

The human studies described here administered material under registered protocols in defined populations under clinical supervision, and in the diagnostic literature under an approved product in one country. None of that research is research into, or evidence about, research-grade material supplied for laboratory use.

Frequently Asked Questions

What is the growth hormone secretagogue receptor?
A class A, rhodopsin-like G protein-coupled receptor identified in 1996 in pituitary and hypothalamus as the receptor through which synthetic growth hormone secretagogues act [6]. Its endogenous ligand, ghrelin, was identified in 1999 as an acylated peptide from the stomach [14]. It is also called the ghrelin receptor; the two names denote the same protein.
Why was the receptor found before its hormone?
Because the drugs came first. A synthetic hexapeptide reported in 1984 released growth hormone from the pituitary by a route the GHRH receptor could not explain [1], which prompted the search for the receptor responsible [6]. The endogenous ligand was identified three years after the receptor [14].
How is it different from the GHRH receptor?
They are different structural families and different pharmacology, converging on the same pituitary cell. The GHRH receptor is a class B1 receptor cloned from human anterior pituitary in 1993 with a conventional peptide ligand [2]. GHS-R1a is class A, its natural ligand is lipidated as a condition of function [14], and it has high constitutive activity [17].
Which compounds act at this receptor?
GHRP-6, the founding member of the growth hormone-releasing peptide family [1]; GHRP-2, a later hexapeptide described in the class literature as more potent [18]; and ipamorelin, a pentapeptide characterised as the first selective secretagogue because in swine it released growth hormone without measurable ACTH or cortisol release [9]. None has a sequence relationship to ghrelin.
What does constitutive activity mean here?
That the receptor signals substantially without any ligand bound. That was shown in 2003 together with the identification of a potent inverse agonist, a compound that reduces signalling below the unliganded baseline [17]. Its practical implication is that pharmacology at this receptor has to account for basal tone, not only for agonist occupancy.
Is anything acting at this receptor approved?
GHRP-2, under the name pralmorelin, is approved in Japan as a diagnostic agent for provocative testing of growth hormone secretion. No compound acting at this receptor is approved in the United States for any indication, diagnostic or therapeutic.
What does the human evidence at this receptor actually measure?
Mostly hormone concentrations. The largest body of human work validates provocative diagnostic thresholds against the insulin tolerance test [19, 23], and the most mechanistically informative studies administer a secretagogue and GHRH to the same participants to distinguish two receptor routes [10]. Therapeutic programmes at this receptor are few, and the two phase 2 trials of ipamorelin in postoperative gastrointestinal function did not publish results [29, 30].

References

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  3. Diagnostic studies with intravenous and intranasal growth hormone-releasing peptide-2 in children of short stature The Journal of Clinical Endocrinology and Metabolism; 1995. PMID 7559885 doi:10.1210/jcem.80.10.7559885
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  10. Growth hormone (GH) response to GH-releasing peptide-6 and GH-releasing hormone in normal-weight and overweight patients with non-insulin-dependent diabetes mellitus Metabolism: Clinical and Experimental; 1999. PMID 10206449 doi:10.1016/s0026-0495(99)90115-4
  11. Tripartite neuroendocrine activation of the human growth hormone (GH) axis in women by continuous 24-hour GH-releasing peptide infusion: pulsatile, entropic, and nyctohemeral mechanisms The Journal of Clinical Endocrinology and Metabolism; 1999. PMID 10372723 doi:10.1210/jcem.84.6.5687
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  16. Acute central ghrelin and GH secretagogues induce feeding and activate brain appetite centers Endocrinology; 2002. PMID 11751604 doi:10.1210/endo.143.1.8561
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  21. Efficacy of ipamorelin, a novel ghrelin mimetic, in a rodent model of postoperative ileus The Journal of Pharmacology and Experimental Therapeutics; 2009. PMID 19289567 doi:10.1124/jpet.108.149211
  22. The positive effects of growth hormone-releasing peptide-6 on weight gain and fat mass accrual depend on the insulin/glucose status Endocrinology; 2010. PMID 20219977 doi:10.1210/en.2009-1394
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  30. Safety and Efficacy of Ipamorelin Compared to Placebo for the Recovery of Gastrointestinal Function. NCT01280344

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