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A kisspeptin-10 analog with greater in vivo bioactivity than kisspeptin-10.

Curtis AE, Cooke JH, Baxter JE, Parkinson JR, Bataveljic A, Ghatei MA, Bloom SR, Murphy KG - Am. J. Physiol. Endocrinol. Metab. (2009)

Bottom Line: The smallest endogenous kisspeptin, kisspeptin-10 (KP-10), binds to the receptor KISS1R with a similar affinity to the full-length peptide, kisspeptin-54 (KP-54), but is less effective in vivo, possibly because of increased enzymatic breakdown or clearance.In addition, 60 min postinjection, 0.15 nmol [dY](1)KP-10 significantly increased total testosterone levels in mice whereas the same dose of KP-10 had no significant effect.Should manipulation of the kisspeptin/KISS1R signaling system prove therapeutically useful, long-lasting analogs such as [dY](1)KP-10 may have greater therapeutic potential than endogenous forms of kisspeptin.

View Article: PubMed Central - PubMed

Affiliation: Dept. of Investigative Medicine, Imperial College London, Hammersmith Hospital Campus, Du Cane Rd., London W12 0NN, UK.

ABSTRACT
The kisspeptins are neuropeptides that stimulate the hypothalamo-pituitary-gonadal (HPG) axis. The smallest endogenous kisspeptin, kisspeptin-10 (KP-10), binds to the receptor KISS1R with a similar affinity to the full-length peptide, kisspeptin-54 (KP-54), but is less effective in vivo, possibly because of increased enzymatic breakdown or clearance. The kisspeptin system may have therapeutic potential in the treatment of reproductive disorders and endocrine cancers. We have rationally modified the structure of KP-10 and tested the binding affinity of these analogs for the KISS1R. Those analogs that bound with relatively high affinity to KISS1R were tested for ability to stimulate ERK1/2 phosphorylation in vitro and for their ability to stimulate the HPG axis in vivo. One analog, [dY](1)KP-10, bound to KISS1R with lower affinity to KP-10 and exhibited similar bioactivity in vitro. However, in vivo peripheral administration of [dY](1)KP-10 increased plasma LH and testosterone more potently than KP-10 itself at 20 min postinjection in mice. In addition, 60 min postinjection, 0.15 nmol [dY](1)KP-10 significantly increased total testosterone levels in mice whereas the same dose of KP-10 had no significant effect. Should manipulation of the kisspeptin/KISS1R signaling system prove therapeutically useful, long-lasting analogs such as [dY](1)KP-10 may have greater therapeutic potential than endogenous forms of kisspeptin.

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Effect of ip administration of analogs ANA5 and ANA8 on plasma total testosterone in male mice at 20 min postinjection. **P < 0.01, ***P < 0.01 vs. saline (ANOVA with post hoc Tukey's adjustment); n = 5–6.
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Figure 4: Effect of ip administration of analogs ANA5 and ANA8 on plasma total testosterone in male mice at 20 min postinjection. **P < 0.01, ***P < 0.01 vs. saline (ANOVA with post hoc Tukey's adjustment); n = 5–6.

Mentions: ANA5 stimulated the release of testosterone at 20 min. However, this effect was not as great as that of KP-10. At a dose of 0.5 nmol, ANA8 did not influence testosterone release. However, at a higher dose of 10 nmol, ANA8 significantly stimulated testosterone release (Fig. 4), suggesting that ANA8 is a weak agonist of the KISS1R, rather than an antagonist.


A kisspeptin-10 analog with greater in vivo bioactivity than kisspeptin-10.

Curtis AE, Cooke JH, Baxter JE, Parkinson JR, Bataveljic A, Ghatei MA, Bloom SR, Murphy KG - Am. J. Physiol. Endocrinol. Metab. (2009)

Effect of ip administration of analogs ANA5 and ANA8 on plasma total testosterone in male mice at 20 min postinjection. **P < 0.01, ***P < 0.01 vs. saline (ANOVA with post hoc Tukey's adjustment); n = 5–6.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC2822479&req=5

Figure 4: Effect of ip administration of analogs ANA5 and ANA8 on plasma total testosterone in male mice at 20 min postinjection. **P < 0.01, ***P < 0.01 vs. saline (ANOVA with post hoc Tukey's adjustment); n = 5–6.
Mentions: ANA5 stimulated the release of testosterone at 20 min. However, this effect was not as great as that of KP-10. At a dose of 0.5 nmol, ANA8 did not influence testosterone release. However, at a higher dose of 10 nmol, ANA8 significantly stimulated testosterone release (Fig. 4), suggesting that ANA8 is a weak agonist of the KISS1R, rather than an antagonist.

Bottom Line: The smallest endogenous kisspeptin, kisspeptin-10 (KP-10), binds to the receptor KISS1R with a similar affinity to the full-length peptide, kisspeptin-54 (KP-54), but is less effective in vivo, possibly because of increased enzymatic breakdown or clearance.In addition, 60 min postinjection, 0.15 nmol [dY](1)KP-10 significantly increased total testosterone levels in mice whereas the same dose of KP-10 had no significant effect.Should manipulation of the kisspeptin/KISS1R signaling system prove therapeutically useful, long-lasting analogs such as [dY](1)KP-10 may have greater therapeutic potential than endogenous forms of kisspeptin.

View Article: PubMed Central - PubMed

Affiliation: Dept. of Investigative Medicine, Imperial College London, Hammersmith Hospital Campus, Du Cane Rd., London W12 0NN, UK.

ABSTRACT
The kisspeptins are neuropeptides that stimulate the hypothalamo-pituitary-gonadal (HPG) axis. The smallest endogenous kisspeptin, kisspeptin-10 (KP-10), binds to the receptor KISS1R with a similar affinity to the full-length peptide, kisspeptin-54 (KP-54), but is less effective in vivo, possibly because of increased enzymatic breakdown or clearance. The kisspeptin system may have therapeutic potential in the treatment of reproductive disorders and endocrine cancers. We have rationally modified the structure of KP-10 and tested the binding affinity of these analogs for the KISS1R. Those analogs that bound with relatively high affinity to KISS1R were tested for ability to stimulate ERK1/2 phosphorylation in vitro and for their ability to stimulate the HPG axis in vivo. One analog, [dY](1)KP-10, bound to KISS1R with lower affinity to KP-10 and exhibited similar bioactivity in vitro. However, in vivo peripheral administration of [dY](1)KP-10 increased plasma LH and testosterone more potently than KP-10 itself at 20 min postinjection in mice. In addition, 60 min postinjection, 0.15 nmol [dY](1)KP-10 significantly increased total testosterone levels in mice whereas the same dose of KP-10 had no significant effect. Should manipulation of the kisspeptin/KISS1R signaling system prove therapeutically useful, long-lasting analogs such as [dY](1)KP-10 may have greater therapeutic potential than endogenous forms of kisspeptin.

Show MeSH
Related in: MedlinePlus