Ranatachykinin A: frog pain-signaling peptide (CHEMBL384518)
A small peptide from the American bullfrog that switches on the same nerve receptor (NK1) involved in pain signaling and gut squeezing in mammals; used only as a laboratory research tool.
A researcher, an agent, or an algorithm wrote down the sequence and picked a target to hit.
An AI model like OpenFold3 or AlphaFold built a 3D structure and scored how well it fits the binding site.
A second contributor repeated the computation on their own hardware and the scores matched.
A chemistry service or a researcher ordered the sequence, it was manufactured, and mass spectrometry confirmed the right molecule was produced.
A binding or activity measurement confirmed that it actually does what the computer predicted — or didn't.
What this is
Ranatachykinin A is an 11-amino-acid neuropeptide first isolated from the brain and intestine of the American bullfrog (Rana catesbeiana). It belongs to the tachykinin family — a group of signaling peptides found across vertebrates that share a conserved C-terminal fingerprint sequence (Phe-X-Gly-Leu-Met) and activate receptors involved in pain signaling, gut contraction, and inflammation. Ranatachykinin A binds the tachykinin NK1 receptor (TACR1), the same receptor targeted by the mammalian peptide substance P. The raw sequence stored here (KPSPDRFYGLM) represents the amino acid backbone; the biologically active form carries a C-terminal amide group (–NH₂) not shown in the single-letter code, which is characteristic of all vertebrate tachykinins and required for receptor binding.
History
Tachykinins as a class were first hinted at in 1931, when von Euler and Gaddum discovered a tissue extract from horse brain and intestine that caused intestinal contraction and vasodilation — a substance they called "P." Substance P's amino acid sequence was not determined until 1971 (Chang, horse intestine). Ranatachykinin A was identified much later, in 1991, when Kozawa and colleagues purified four novel tachykinins from bullfrog (Rana catesbeiana) brain and intestine (Kozawa et al., Biochemical and Biophysical Research Communications, 1991). All four peptides — ranatachykinins A, B, C, and D — displayed potent stimulant effects on guinea pig ileum smooth muscle, a classic bioassay for tachykinin activity. The structural and pharmacological properties of ranatachykinin A at the cloned bullfrog substance P receptor were characterised in detail by Perrine and colleagues (Perrine et al., Journal of Medicinal Chemistry, 2000).
What it does
Ranatachykinin A activates NK1 receptors on smooth muscle, neurons, and immune cells, triggering a cascade of responses including muscle contraction, pain signal amplification, and inflammatory cell recruitment. At the bullfrog substance P receptor expressed in cell culture, ranatachykinin A shows potency at least equal to substance P itself — the rank order of agonist activity across the three canonical ranatachykinins was RTKA ≥ SP > RTKC ≥ RTKB (Perrine et al. 2000). In bullfrog sensory neurons, tachykinins activate NK1 receptors to suppress potassium channels and generate inward electrical currents, which is thought to underlie their role in sensory transmission (Tachykinins cause inward current through NK1 receptors in bullfrog sensory neurons, 1996).
Evidence
- Human: No human trials exist for ranatachykinin A itself. It has been studied as a pharmacological tool to probe the bullfrog substance P receptor and to compare tachykinin structural diversity across species.
- Animal: Ranatachykinin A was shown to stimulate guinea pig ileum smooth muscle contraction with potent activity (Kozawa et al. 1991). At the cloned bullfrog substance P receptor (bfSPR) transfected into Chinese hamster ovary cells, ranatachykinin A produced calcium mobilisation responses comparable to or exceeding those of substance P (Perrine et al. 2000). The receptor cloned from bullfrog sympathetic ganglion showed 69% sequence identity to mammalian substance P receptors and responded to tachykinin agonists in the order SP > NKA >> NKB (Molecular characterization of a substance P receptor from Rana catesbeiana sympathetic ganglion, 1997).
- In vitro: EC50 = 0.6 nM at TACR1 (ChEMBL bioassay, CHEMBL384518).
Mechanism
TACR1 (NK1 receptor) is a G protein-coupled receptor that primarily signals through Gq/11, activating phospholipase C to generate inositol trisphosphate (IP3) and diacylglycerol, raising intracellular calcium. Downstream effects include ERK1/2 phosphorylation via protein kinase C, NF-κB-mediated inflammatory gene expression, and PI3K/Akt cell-survival signalling (Garcia-Recio and Gascón, BioMed Research International, 2015). The critical pharmacophore in all tachykinins is the C-terminal Phe-X-Gly-Leu-Met-NH₂ sequence, which docks into the orthosteric binding site of the receptor; the N-terminal residues modulate receptor subtype selectivity and signalling bias but are dispensable for activation. NMR studies of ranatachykinin A and its bullfrog relatives in SDS micelles revealed a helical conformation spanning the midregion to C-terminus (residues 4–10), with a flexible N-terminus — a structure that may account for the differences in desensitisation kinetics observed between RTKA and RTKC (Perrine et al. 2000).
Related peptides
The tachykinin family at TACR1 includes substance P (the canonical human NK1 agonist) and a range of amphibian and invertebrate variants that have been used to map receptor binding determinants. Other ranatachykinins (B, C, D) were isolated alongside RTKA from the same bullfrog tissue preparation (Kozawa et al. 1991) and differ primarily in their N-terminal residues and in the identity of the variable position within the conserved C-terminal motif.
Research directions for this peptide, selected from the current sources — hypotheses you can explore and model. None of it is proven yet; tap any one to see the full thinking.
Does the frog version of substance P stick to one pain receptor subtype while avoiding others?
If it turns out to favor NK1, this frog peptide could be a cleaner tool for studying NK1-specific pain signaling. Note: this is an untested prediction; the acidic residue is at position 5 (Asp), not 6, and selectivity has not yet been measured.
Can this frog intestine peptide be used to model the gut signaling involved in nausea and bowel disease?
Because it came from frog intestine and acts on gut NK1 receptors, ranatachykinin A could be a probe for the NK1-serotonin pathway that drives nausea and abnormal gut contractions. The idea that it avoids receptor desensitization is an added guess that would need checking.
Can chemists swap the frog peptide's non-binding end to make a targeted carrier for NK1-expressing cancers?
Because the N-terminus is not the binding pharmacophore, it can likely be replaced, mirroring existing NK1-targeted substance P analogs used against tumors that overexpress NK1. The binding end itself already provides the tumor-homing, so this is an engineering extension of a known approach.
Can a short fragment of this frog peptide still trigger the NK1 pain receptor?
For tachykinins it is already well known that the C-terminal five residues drive receptor activation, so a short FYGLM-NH2 fragment likely retains activity. Confirming this for ranatachykinin A would let chemists treat the front end as a separate handle for stability or targeting.
Does this frog pain peptide last longer in the body than the equivalent human peptide?
An N-terminal proline can slow aminopeptidase trimming, so ranatachykinin A could be somewhat more stable at its front end. But ACE and neprilysin are not aminopeptidases and they cut at the shared C-terminal region, so broad protease resistance is not established and would need direct testing.
▸full evidence table1 metrics
| metric | value | tool |
|---|---|---|
| EC50 | 0.6 nM | GPCRDB/ChEMBL |
▸3-letter notation
▸recipeboltz-2 2.2.1
| parameter | value |
|---|---|
| model | boltz-2 2.2.1 |
| weights | — |
| hardware | vast_v100_32gb |
| mlx version | — |
| python | — |
| random seed | 1 |
| msa strategy | colabfold_local |
| runtime | — |
| predicted by | — |
| predicted at | 2026-05-22 |
▸citationbibtex
@peptide{pep10454,
sequence = {KPSPDRFYGLM},
target = {tacr1},
author = {peptidemodel},
year = {2026},
status = {bioassayed}
}