Chemical Identity

Property	Value
Name	Substance P
Gene	TAC1 (preprotachykinin A)
Sequence	Arg-Pro-Lys-Pro-Gln-Gln-Phe-Phe-Gly-Leu-Met-NH₂
Abbreviation	RPKPQQFFGLM-NH₂
Length	11 amino acids
Chemical Formula	C₆₃H₉₈N₁₈O₁₃S
Molecular Weight	1347.6 Da
pI	~11.5
CAS Number	33507-31-2
PDB Structures	1T8N (NMR), 1SBP (NMR)

Classification

Substance P belongs to the tachykinin family of neuropeptides, characterized by:

• C-terminal sequence: -Phe-X-Gly-Leu-Met-NH₂ (tachykinin consensus)
• Gene family: TAC1 (encodes substance P, neurokinin A, and neuropeptide K)
• Receptor: Neurokinin-1 receptor (NK1R, TACR1 gene)

Tachykinin	Sequence	Receptor
Substance P	RPKPQQFFGLM-NH₂	NK1
Neurokinin A	HKTDSFVGLM-NH₂	NK2
Neurokinin B	DMHDFFVGLM-NH₂	NK3

Distribution

Central Nervous System

• Dorsal horn of spinal cord: Primary afferent C-fibers and Aδ-fibers
• Brainstem: Nucleus tractus solitarius, periaqueductal gray
• Hypothalamus: Paraventricular nucleus
• Limbic system: Amygdala, hippocampus

Peripheral Nervous System

• Sensory neurons: DRG neurons (30-40% of small DRG neurons)
• Autonomic neurons: Sympathetic and parasympathetic
• Enteric nervous system: Myenteric and submucosal plexus

Other Tissues

• Immune cells: T-cells, monocytes, macrophages
• Inflammatory cells: Mast cells, eosinophils
• Endothelial cells: Vascular endothelium

Biosynthesis

Substance P is derived from the preprotachykinin A (PPTA) precursor:

1. Gene: TAC1 (chromosome 7q21-q22)
2. mRNA splicing: Produces α-PPTA and β-PPTA mRNA
3. Translation: Preprotachykinin A (140 aa)
4. Signal peptide cleavage: Signal peptidase → pro-tachykinin
5. Proteolytic processing: Prohormone convertases → Substance P
6. Storage: Large dense-core vesicles
7. Release: Ca²⁺-dependent exocytosis

Receptor and Signaling

NK1 Receptor (TACR1)

• Type: Class A G-protein coupled receptor
• Expression: Brain, spinal cord, immune cells, enteric neurons
• G-protein coupling: Gαq/11 → PLC → IP₃ + DAG → Ca²⁺ + PKC
• Desensitization: Phosphorylation by GRKs, β-arrestin recruitment, internalization

Signal Transduction

Substance P → NK1R → Gαq → PLCβ → IP₃ + DAG
                                    ↓
                              IP₃ → Ca²⁺ release
                              DAG → PKC activation
                                    ↓
                              NF-κB, MAPK, CREB

Physiological Functions

Pain Transmission (Nociception)

• Role: Primary neurotransmitter for nociceptive C-fibers
• Mechanism: Released from primary afferents → activates NK1R on dorsal horn neurons → pain signal propagation
• Evidence: Substance P knockout mice show reduced pain behavior; NK1R antagonists (aprepitant) are analgesic

Neurogenic Inflammation

• Vasodilation: Increases vascular permeability
• Plasma extravasation: Protein leakage from blood vessels
• Mast cell degranulation: Histamine release
• Neutrophil activation: Cytokine production

Mood Regulation

• Anxiety: Substance P in amygdala modulates fear and anxiety
• Depression: NK1R antagonists show antidepressant effects
• Mechanism: Modulates serotonin and norepinephrine pathways

Clinical Significance

Aprepitant (Emend®)

• Type: NK1R antagonist
• Indication: Chemotherapy-induced nausea and vomiting (CINV)
• Mechanism: Blocks substance P signaling in the emetic center
• Approval: FDA 2003

Other NK1R Antagonists

Drug	Indication	Status
Fosaprepitant (Ivemend®)	CINV (IV)	Approved
Netupitant (Akynzeo®)	CINV	Approved
Rolapitant (Varubi®)	CINV	Approved
Emapitant (Emend®)	CINV	Approved
Saredutant	Depression	Phase III (discontinued)

Research Applications

• Pain models: Intrathecal substance P for pain research
• Inflammation models: Subcutaneous injection for neurogenic inflammation
• Neuroprotection: Substance P and analogs in neuroprotection studies
• Biomarker: CSF substance P levels in chronic pain conditions

References

1. Otsuka M, Kawasaki H. “Neuropeptides and pain pathways.” Annual Review of Neuroscience 13:109-133, 1992. doi:10.1146/annurev.ne.13.030191.001545
2. Harrison S, Geppetti P. “Substance P.” International Journal of Biochemistry and Cell Biology 33:555-575, 2001. doi:10.1016/S1357-2725(01)00046-5
3. DeFea KA, et al. “Beta-arrestin-dependent endocytosis of proteinase-activated receptor-2.” Journal of Biological Chemistry 275:25037-25044, 2000.
4. Holmes A, et al. “Substance P and NK1 receptor antagonists: novel approaches to anxiety and depression.” Current Drug Targets - CNS and Neurological Disorders 2:287-297, 2003.
5. Severini C, et al. “Pharmacology of tachykinin peptides.” Pharmacological Reviews 52:31-69, 2000.