Description
Summary Abstract
Kisspeptin-10 (KP-10; Metastin (45–54); CAS 374675-21-5) is a synthetic decapeptide corresponding to the C-terminal bioactive fragment of the KISS1 gene product. It is the shortest peptide fragment retaining maximal activity at the kisspeptin receptor KISS1R (also known as GPR54), a Gαq/11-coupled receptor expressed on hypothalamic gonadotropin-releasing hormone (GnRH) neurons. Kisspeptin signaling is an essential upstream regulator of the hypothalamic-pituitary-gonadal (HPG) axis: loss-of-function mutations of GPR54 produce hypogonadotropic hypogonadism and absent puberty in humans and mice. KP-10 is among the most potent endogenous stimulators of LH release across mammalian species, with central effective doses as low as 1–2 femtomoles. It has entered Phase III clinical development for reproductive and endocrine indications and is a validated standard tool for neuroendocrine axis research.
Clinical Indications
KP-10’s central role in the HPG axis supports investigation across several reproductive endocrinology contexts:
- Hypogonadotropic Hypogonadism: Kisspeptin-10 IV bolus (1 µg/kg) produces a rapid, dose-dependent rise in serum LH and increases LH pulse frequency in men, establishing its utility as a diagnostic and mechanistic probe for GPR54-dependent GnRH regulation.
- Puberty Onset and Reproductive Axis Activation: KISS1/GPR54 mutations impair pubertal GnRH surge generation; KP-10 is the standard pharmacological tool for characterizing hypothalamic kisspeptin neuron function, sex steroid feedback, and KNDy (kisspeptin/neurokinin B/dynorphin) neuron dynamics.
- Insulin Secretion Research: KP-10 is currently under investigation in clinical trial NCT03771326 for effects on insulin secretion in men, reflecting emerging evidence for kisspeptin signaling in pancreatic β-cell function beyond reproductive biology.
Contraindications
- Continuous Infusion Desensitization: Continuous kisspeptin-10 administration produces receptor desensitization and KISS1R internalization within 24 hours, suppressing rather than stimulating LH release; protocols should account for GRK2/β-arrestin-mediated tachyphylaxis in long-duration designs.
- Sex Steroid-Dependent Response Variability: KP-10 efficacy at the hypothalamic level is strongly modulated by gonadal steroid concentrations; studies in hypogonadal or castrated models may require dose adjustments relative to intact controls.
- Anti-angiogenic Activity: Kisspeptin-10 inhibits VEGF-mediated HUVEC proliferation and migration; investigators designing studies in models with active angiogenesis should account for potential off-target effects on vascular endpoints.
Mechanism of Action (MOA)
KP-10 exerts its biological effects through high-affinity engagement of KISS1R on hypothalamic GnRH neurons and peripheral reproductive tissues:
KISS1R / GPR54 Activation
KP-10 binds the orthosteric site of KISS1R (GPR54) with Ki values of 1.59 nM (rat) and 2.33 nM (human), activating Gαq/11 protein dissociation. Activated Gαq/11 stimulates phospholipase C-β, hydrolyzing PIP2 to DAG and IP3, mobilizing intracellular calcium and depolarizing GnRH neurons via TRPC channel activation.
GnRH Release and HPG Axis Stimulation
Kisspeptin-10 binding to KISS1R on GnRH neurons directly stimulates pulsatile GnRH release into the hypophyseal portal circulation within minutes. GnRH then acts on pituitary gonadotrophs to drive LH and FSH secretion. KP-10 is among the most potent known endogenous GnRH secretagogues, with central ED50 of 2–4 pmol and systemic threshold of ~0.1 µg/rat.
ERK1/2 and β-Arrestin Signaling
KISS1R activation also phosphorylates ERK1/2 and p38 MAPK through both G protein-dependent and β-arrestin-dependent pathways. β-Arrestin-1 promotes ERK1/2 phosphorylation while β-arrestin-2 inhibits it, providing a dual regulatory axis that modulates receptor internalization and downstream transcriptional responses in both reproductive and non-reproductive tissues.
Key Features & Specifications
KP-10 is the reference pharmacological tool for KISS1R/GPR54 biology and hypothalamic reproductive neuroendocrinology:
Chemical Analysis
| Property | Specification Reference Data |
|---|---|
| Sequence | Tyr-Asn-Trp-Asn-Ser-Phe-Gly-Leu-Arg-Phe-NH2 |
| CAS Number | 374675-21-5 |
| Molecular Formula | C63H83N17O14 |
| Molecular Weight | 1302.45 g/mol |
| PubChem CID | 25240297 |
| Synonyms | KP-10, Metastin (45–54), Kisspeptin (human), KISS1(112–121) |
| Form / Variation | 10 MG Lyophilized (SKU P-022) |
Storage, Safety, and Handling
Storage Protocol
Store lyophilized KP-10 at −20 °C in a sealed, desiccated container, protected from light. Reconstitute in sterile bacteriostatic water or aqueous buffer; maintain reconstituted peptide at 4 °C and use within 28 days. Freezing after reconstitution risks aggregation; prepare working aliquots to minimize freeze-thaw cycles.
Handling & Compliance
Standard laboratory PPE applies. Kisspeptin-10 is a potent endogenous neuroendocrine peptide; protocols involving its administration should include monitoring of LH/FSH levels and account for potential effects on steroidogenesis in any model with intact HPG axis function. WADA classification should be confirmed for studies involving competitive athletes, as peptide hormones affecting the gonadotropic axis are subject to regulatory scrutiny.