Kisspeptin: Mechanism of Action

Mechanism of Action

KISS1R (GPR54) Receptor Binding

Kisspeptin acts by binding KISS1R (GPR54/AXOR12), a rhodopsin-like Class A GPCR sharing ~45% identity with galanin receptors (but does not bind galanin). The essential pharmacophore is the C-terminal RF-amide motif; key residues Phe-6 and Arg-9 (Kp-10 numbering) are critical for binding. Cryo-EM studies reveal an orthosteric pocket spanning TM2–7 plus ECL1–3.[2][3]

Primary Gαq/11–PLC–Ca²⁺ Pathway

KISS1R couples primarily to Gαq/11, activating phospholipase C beta (PLCβ), which hydrolyzes PIP₂ into IP₃ and DAG. IP₃ triggers biphasic intracellular Ca²⁺ release from the endoplasmic reticulum; DAG + Ca²⁺ activates PKC.[8]

MAPK and Additional Cascades

Downstream signaling involves robust, sustained ERK1/2 phosphorylation (via PKC-dependent and β-arrestin pathways), p38 MAPK activation, arachidonic acid release, and PI3K/Akt signaling.[8]

GnRH Neuronal Excitation

In GnRH neurons, kisspeptin activates TRPC channels (cation influx) and simultaneously closes Kir channels (preventing K⁺ efflux), causing sustained depolarization and increased action potential firing → pulsatile GnRH secretion → LH/FSH release.[8]

Desensitization (β-Arrestin–Mediated)

Continuous kisspeptin exposure recruits β-arrestin 1/2, causing receptor internalization via clathrin-coated pits → paradoxical HPG axis suppression. This is exploited therapeutically: TAK-448 continuous exposure suppresses testosterone to castrate levels for prostate cancer research.[9][14]

Isoform Pharmacokinetic Comparison

Isoform	Half-Life	Route	Notes
Kp-54	~27.6 min	IV	Major circulating form; SC extends to ~1.7h
Kp-10	~4 min	IV	Full intrinsic bioactivity; highly conserved
MVT-602 (TAK-448)	Peak at ~21h	SC	MMP-resistant; >4x AUC vs Kp-54