GHRP-6
Growth Hormone Releasing Peptide-6, Growth hormone-releasing hexapeptide, His-D-Trp-Ala-Trp-D-Phe-Lys-NH2
Over-expression of the truncated ghrelin receptor polypeptide attenuates the constitutive activation of phosphatidylinositol-specific phospholipase C by ghrelin receptors but has no effect on ghrelin-stimulated extracellular signal-regulated kinase 1/2 activity.
Chu. Kit-Man KM; Chow. Kevin B S KB; Leung. Po-Ki PK; Lau. Pui-Ngan PN; Chan. Chi-Bun CB; Cheng. Christopher H K CH; Wise. Helen H
Key Findings
- Ghrelin triggers ERK1/2 activation at low nanomolar concentrations, and this effect is blocked by the antagonists D‑Lys3‑GHRP‑6 and a modified substance‑P peptide.
- The ERK1/2 response does not involve calcium, typical PKC isoforms, or transactivation of the epidermal growth factor receptor; it appears to rely on a novel PKC pathway.
- A truncated ghrelin‑receptor polypeptide reduces the receptor’s constitutive (always‑on) activation of phosphatidylinositol‑specific PLC, but does not affect ghrelin‑stimulated ERK1/2 signaling.
Practical Outcomes
- For biohackers using GHRP‑6, the data suggest that the peptide’s main signaling effect (ERK activation) is robust and not easily dampened by receptor internalization, implying consistent downstream activity. The finding that a truncated receptor can curb baseline PLC activity hints at a possible way to reduce unwanted side‑effects linked to constant receptor activation, though no direct dosing or protocol changes are derived from this study.
Summary
The study shows how ghrelin (the hormone that GHRP‑6 mimics) activates a specific cell‑signaling route (ERK1/2) in kidney cells, and that this activation is blocked by certain ghrelin‑receptor antagonists. It also finds that a shortened version of the ghrelin receptor can dial down the receptor’s baseline activity without changing the hormone‑driven response.
Abstract
In addition to regulating growth hormone release from the pituitary, ghrelin receptors also influence cell proliferation and apoptosis. By studying mitogen-activated protein kinase activity in human embryonic kidney 293 cells over-expressing ghrelin receptors, we aimed to identify the specific cell signalling pathways used by ghrelin receptors, and to determine if the truncated ghrelin receptor polypeptide had any influence on the functional activity of ghrelin receptors. We found that ghrelin activated extracellular signal-regulated kinases 1/2 with an EC50 value of 10 nM, and that this response was inhibited by the ghrelin receptor antagonists D-Lys3-GHRP-6 and [D-Arg1,D-Phe5,D-Trp(7,9),Leu11]-substance P. Ghrelin had little or no effect on the activity of c-Jun N-terminal kinase, p38 kinase or Akt. Ghrelin appeared to activate extracellular signal-regulated kinases 1/2 through a calcium-independent novel protein kinase C isoform which may utilize diacylglycerol derived from hydrolysis of phosphatidylcholine rather than from phosphatidylinositol. Ghrelin-stimulated extracellular signal-regulated kinases 1/2 activity was independent of transactivation of epidermal growth factor receptors, and even when ghrelin receptor internalization was blocked by concanavalin A or a beta-arrestin mutant, there was no decrease in phosphorylated extracellular signal-regulated kinases 1/2, suggesting this is a G protein-dependent process. The truncated ghrelin receptor polypeptide had no effect on ghrelin receptor signalling to extracellular signal-regulated kinases 1/2, but decreased the constitutive activation of phosphatidylinositol-specific phospholipase C by ghrelin receptors. In conclusion, our results suggest that any up-regulation of the truncated ghrelin receptor polypeptide might preferentially attenuate functional activity dependent on the constitutive activation of ghrelin receptors, while leaving ghrelin-dependent signalling unaffected.
Study Information
pubmed
2006
2006-11-23T00:00:00.000Z
10.1016/j.biocel.2006.11.007