Mechanism of Action
Tachykinin Receptor Selectivity
Endokinin A and B share the C-terminal decapeptide GKASQFFGLM-NH2 and activate NK1, NK2, and NK3 receptors, with preference for NK2 and NK3 vs substance P which prefers NK1. All tachykinin receptors are Gq-coupled GPCRs activating phospholipase C, elevating IP3 and intracellular calcium. NK2 activation causes smooth muscle contraction; NK3 activation modulates neurotransmitter release in the CNS. Endokinin C and D are shorter fragments with distinct receptor profiles.
Placental and Reproductive Expression
The TAC4 gene is highly expressed in placenta, with endokinin levels rising dramatically during pregnancy. Endokinins may participate in uteroplacental blood flow regulation and parturition signaling. High TAC4 expression in trophoblasts suggests roles in implantation and placental development not shared by other tachykinins.
Research Summary
Pain and Neurogenic Inflammation
PreclinicalEndokinins released from sensory nerve terminals contribute to neurogenic inflammation and pain transmission similar to substance P. EKA and EKB activate NK1 receptors on spinal dorsal horn neurons to facilitate pain signaling. NK2/NK3 receptor activation by endokinins modulates neurotransmitter release and pain sensitization in chronic pain models.
Reproductive Biology
PreclinicalEndokinin expression in placenta and uterus, combined with upregulation during pregnancy, suggests roles in parturition. Kisspeptin-neurokinin B-dynorphin (KNDy) neurons in the hypothalamus regulate GnRH pulses; endokinins may interact with this system as TAC4-derived peptides with overlapping NK receptor activity.
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Research Protocols
| Goal | Dose | Frequency | Route |
|---|---|---|---|
| NK1/NK2/NK3 receptor pharmacology (in vitro) | 1-1000 nM | Single concentration-response | Cell-based receptor assay |
| Neurogenic inflammation (rodent) | 10-100 nmol/kg IV | Single injection | Intravenous |
| Nociception (rodent) | 1-10 nmol ICV | Single injection | Intracerebroventricular |
Endokinins are pharmacological research tools for tachykinin receptor biology. No clinical development. Used primarily to dissect NK2/NK3 contributions separate from NK1-dominant substance P.
Interactions
Safety Profile
No human safety data for exogenous endokinin administration. As tachykinins, endokinins cause vasodilation, smooth muscle contraction, and pro-inflammatory effects at pharmacological doses similar to other tachykinins. The well-characterized safety of NK1 antagonists (aprepitant, netupitant) used clinically for nausea supports the safety of blocking tachykinin signaling. No commercial product exists.
References
- [1]Page NM, et al. Characterization of the endokinins: human tachykinins with cardiovascular activity. Proc Natl Acad Sci USA. 2003;100(10):6245-6250.
- [2]Page NM. New challenges in the study of the mammalian tachykinins. Peptides. 2005;26(8):1356-1368.
- [3]Pennefather JN, et al. Tachykinins and tachykinin receptors: a growing family. Life Sci. 2004;74(12):1445-1463.