Truncated Versions of Substance P and Neurokinin A Reveal Signaling Bias at Tachykinin Receptors | Research

The takeaway

Progressively truncated substance P and neurokinin A analogs show altered signaling profiles at NK1 and NK2 receptors, challenging assumptions about peptide-receptor activity.

SP(6-11) still active
Even the shortest truncated substance P fragment retained activity at NK1 receptors but with altered signaling bias

What the researchers found

Truncated tachykinin analogs retain receptor activity but show altered signaling bias at NK1R and NK2R, with the shortest functional versions being SP(6-11) and NKA(5-10).

Why it matters

Understanding how peptide length affects receptor signaling helps design drugs that activate beneficial pathways while avoiding harmful ones — key for developing safer tachykinin-based therapies.

The numbers in context

12 SP analogs and 10 NKA analogs tested. SP(6-11) and NKA(5-10) shortest versions. Measured cAMP (Gs) and IP3 (Gq) accumulation via BRET assays at NK1R and NK2R.

How the study worked

In vitro receptor pharmacology study progressively truncating SP and NKA, testing signaling activity at NK1R and NK2R with free and acetylated N-terminal variants.

Who was studied

Not applicable (receptor pharmacology)

What this study cannot tell us

In vitro study — signaling bias in cell assays may not directly predict in vivo pharmacological effects. Only two receptor subtypes were studied.

How to read the evidence

In vitro receptor pharmacology study — rigorous for understanding receptor biology but therapeutic applications remain theoretical.

When this study was published

Published in 2025 in the Journal of Biological Chemistry.

The bigger picture

This work demonstrates that peptide fragments can have different therapeutic profiles than their parent molecules, opening doors for designing biased agonists from natural neuropeptides.

Questions still open

Can truncated tachykinin analogs be developed as biased agonists for specific therapeutic applications?
How does acetylation of the N-terminus affect receptor selectivity and signaling?

Common questions

What are tachykinins?

Tachykinins are a family of neuropeptides including substance P and neurokinin A that are involved in pain transmission, inflammation, and many other physiological processes. They work by activating NK1 and NK2 receptors.

What is signaling bias?

Signaling bias means a drug or peptide activates some pathways through a receptor more than others. This is important because different pathways can produce beneficial or harmful effects, so biased drugs could be safer than non-selective ones.

Read the original research

Challenging activity and signaling bias in tachykinin NK1 and NK2 receptors by truncated neuropeptides.

The Journal of biological chemistry, 301(6), 108522

View on PubMed ↗Publisher’s paper ↗

Citation

Petersen, Jacob E; Pavlovskyi, Artem; Madsen, Jesper J; Schwartz, Thue W; Frimurer, Thomas M; Olsen, Ole H. (2025). Challenging activity and signaling bias in tachykinin NK1 and NK2 receptors by truncated neuropeptides.. The Journal of biological chemistry, 301(6), 108522. https://doi.org/10.1016/j.jbc.2025.108522