Hexarelin and MK-0677 Reveal Widespread GHS Receptor Distribution Across Human Peripheral Tissues
Background
Growth hormone secretagogues (GHS) are a family of molecules that stimulate GH release via specific receptors, with GHSR identified in the brain, pituitary, and thyroid. A cardiac-specific GHSR subtype was previously detected in the heart, and the discovery of ghrelin — a gastric-derived endogenous peptide — as a natural ligand added complexity to understanding peripheral GHS signaling. However, no comprehensive map of GHS receptor distribution across human peripheral tissues existed, leaving a critical gap in understanding where peptidyl versus non-peptidyl GHS exert their biological effects and whether distinct receptor subtypes mediate tissue-specific responses.
Study Design
Investigators performed a radioreceptor assay using [125I]Tyr-Ala-hexarelin as radioligand to probe GHS binding sites across a wide panel of human peripheral tissues. Displacement experiments were conducted with three competing agents: hexarelin (peptidyl GHS), MK-0677 (non-peptidyl GHS), and human ghrelin (endogenous ligand). Tissues screened spanned endocrine and non-endocrine categories, including myocardium, adrenal, gonads, arteries, lung, liver, skeletal muscle, kidney, pituitary, thyroid, adipose tissue, veins, uterus, skin, lymph node, parathyroid, pancreas, placenta, mammary gland, prostate, salivary gland, stomach, colon, and spleen.
Results
GHS binding sites were detected in 15 tissue types, with the highest binding activity found in the myocardium, followed in decreasing order by adrenal, gonads, arteries, lung, liver, skeletal muscle, kidney, pituitary, thyroid, adipose tissue, veins, uterus, skin, and lymph node. Negligible binding was observed in parathyroid, pancreas, placenta, mammary gland, prostate, salivary gland, stomach, colon, and spleen.
In endocrine tissues, hexarelin, MK-0677, and human ghrelin all completely displaced [125I]Tyr-Ala-hexarelin, but MK-0677 and ghrelin were less potent than hexarelin.
In non-endocrine tissues, both MK-0677 and ghrelin were inactive as displacing agents, whereas hexarelin retained full displacement activity comparable to its potency in endocrine tissues. This differential displacement pattern across tissue types suggests the existence of a GHSR subtype — specific to peptidyl GHS — that is pharmacologically distinct from the classical GHSR-1a activated by both peptidyl and non-peptidyl ligands.
Key Findings
- GHS binding sites detected in 15 human tissue types; myocardium shows highest receptor density.
- Negligible binding found in 9 tissues including pancreas, stomach, colon, placenta, and prostate.
- Hexarelin, MK-0677, and ghrelin all fully displaced radioligand in endocrine tissues; MK-0677 and ghrelin were less potent than hexarelin.
- MK-0677 and ghrelin showed no displacement activity in non-endocrine tissues; hexarelin remained fully active.
- Data suggest a novel peptidyl GHS-specific receptor subtype exists in heart and non-endocrine peripheral tissues.
Why It Matters
Hexarelin and MK-0677 do not bind to the same receptor populations in peripheral tissues — a distinction with direct implications for anyone selecting between peptidyl and non-peptidyl GHS compounds. For cardiovascular-focused applications, the predominance of GHS binding in the myocardium reinforces cardiac tissue as a primary site of action, independent of GH axis effects. Clinically, the inactivity of MK-0677 and ghrelin in non-endocrine displacement suggests that orally active GHSR agonists like MK-0677 may not replicate all peripheral actions of hexarelin, particularly in cardiac and vascular contexts. For stack or protocol design, this implies that combining or substituting peptidyl and non-peptidyl GHS compounds is not pharmacologically equivalent across all tissue targets.
