Substance P and Neurokinin Receptor Biology

Substance P is a member of the tachykinin family of neuropeptides, characterised by an eleven-amino-acid sequence that is highly conserved across mammalian species. It exerts its effects primarily through the G-protein-coupled neurokinin-1 receptor (NK1R), although lower-affinity binding to neurokinin-2 and neurokinin-3 receptors (NK2R, NK3R) also occurs under certain physiological or pathological conditions. Upon agonist binding, NK1R triggers Gq/11-dependent activation of phospholipase C and subsequent intracellular calcium mobilisation, as well as downstream engagement of mitogen-activated protein kinases (notably ERK1/2) and β-arrestin scaffolds. This pleiotropic signalling network underlies substance P’s roles in nociception, neurogenic inflammation, smooth muscle contractility, neuroimmune communication and central nervous system processes such as stress, anxiety and emesis. Beyond homeostatic function, aberrant substance P–NK1R activity has been implicated in chronic inflammatory states, neuropathic pain, psychiatric disorders, tumourigenesis and tumour progression. Antagonism of NK1R has thus emerged as a compelling therapeutic strategy, with small-molecule antagonists already approved for chemotherapy-induced nausea and vomiting, and further drug repurposing efforts targeting oncology, neuroinflammatory and gastrointestinal disorders. Current research aims to elucidate receptor crosstalk, heterodimerisation with NK2R or other GPCRs, and the cell-type-specific outcomes of substance P signalling in health and disease.

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Substance P and Neurokinin Receptor Biology publication trend

The graph below shows the total number of articles in substance p and neurokinin receptor biology across all publications each year (not limited to Nature Index journals).

Technical terms

Substance P: An eleven-amino-acid neuropeptide of the tachykinin family that acts as the principal ligand for NK1R.

Neurokinin-1 Receptor (NK1R): A G-protein-coupled receptor with high affinity for substance P, mediating diverse intracellular signalling cascades.

Heterodimerisation: The formation of a complex between two different receptor subtypes (for example, NK1R and NK2R) that modulates downstream signalling.

β-Arrestin: A cytosolic adaptor protein that terminates G-protein signalling and scaffolds alternative pathways such as ERK activation.

Aprepitant: A non-peptide NK1R antagonist used clinically to prevent chemotherapy-induced nausea, now under investigation for anticancer repurposing.

References

1. Substance P receptor signaling contributes to host maladaptive responses during enteric bacterial infection. Proceedings of the National Academy of Sciences of the United States of America (2025).
2. Neurokinin-2 receptor negatively modulates substance P responses by forming complex with Neurokinin-1 receptor. Cell & Bioscience (2023).
3. The Repurposing of Non-Peptide Neurokinin-1 Receptor Antagonists as Antitumor Drugs: An Urgent Challenge for Aprepitant. International Journal of Molecular Sciences (2023).