Substance P


Substance P (SP) is an 11 amino acid bioactive peptide that causes diverse biological effects in the central nervous system (CNS), as well as in the cardiovascular, respiratory, gastrointestinal, immune and autonomic nervous systems. The principal actions of SP are mediated through its functional interaction with the neurokinin‐1 (NK‐1) receptor, which exists in two isoforms. Investigators are currently focusing on the structure–activity relationships between SP and the different NK‐1 receptor isoforms, as well as the signal transduction pathways involved in the many SP‐mediated responses. In addition, nonpeptide antagonists of SP have been and are continuing to be developed for clinical use. This article summarizes the basic biology of SP and its interaction with the NK‐1 receptor, highlights the role of SP and the neurokinin receptors in clinical disease states and then concludes with describing new exciting areas of SP‐related research.

Key Concepts:

  • Substance P is an 11 amino acid bioactive peptide that induces diverse biological responses.

  • The principal receptor for substance P is the neurokinin‐1 receptor, which exists in two isoforms.

  • Antagonists of substance P and the neurokinin‐1 receptor have been and are continuing to be developed for clinical use.

  • Research in the area of substance P and the neurokinin‐1 receptor continues to provide more insight into the importance of these molecules in states of human health and disease.

Keywords: neuropeptide; tachykinin; pain; inflammation

Figure 1.

Expression of the mammalian tachykinins and their receptors. The three known mammalian tachykinins (substance P (SP), neurokinin A (NKA) and neurokinin B (NKB)) are derived from the preprotachykinin A (PPT‐A) and B (PPT‐B) genes. Although both substance P and NKA are derived from differential RNA processing of the PPT‐A gene, only NKB is derived from the PPT‐B gene. Following transcription and RNA processing, the α‐PPT‐A mRNA is located only in the nervous system, whereas the β‐PPT‐A mRNA, γ‐PPT‐A mRNA and the PPT‐B mRNA are found in both the nervous system and in the peripheral tissues. The receptors for the tachykinins also have a nonuniform distribution. The NK‐1 and NK‐3 receptors are located both in the nervous system and in the peripheral tissues, whereas the NK‐2 receptor is found only in the peripheral tissues. Adapted from Ohkubo and Nakanishi .

Figure 2.

Differential processing of the preprotachykinin A (PPT‐A) gene. Differential RNA splicing of the PPT‐A gene generates substance P (SP), neurokinin A (NKA), neurokinin A (3–10), neuropeptide K and neuropeptide γ. The pattern of alternative splicing is regulated in a tissue‐specific manner, and the generation of the mature functional peptides proceeds in the following manner: (1) transcription and RNA processing of the PPT‐A gene; (2) translation of the mRNAs into precursor proteins and (3) posttranslational processing of the precursor proteins. The β‐ and γ‐PPT‐A mRNAs constitute 99% of the total human PPT‐A mRNA. Adapted from Helke et al..

Figure 3.

Schematic model of the rat NK‐1 receptor membrane topography. The rat NK‐1 receptor contains an extracellular N‐terminus, seven putative hydrophobic membrane‐spanning domains, intervening extracellular loops (E1, E2 and E3) and intracellular loops (C1, C2, C3 and a possible C4 due to Cys residue palmitoylation) and an intracellular C‐terminus. Asn14 and Asn18 are indicated as putative sites of Asn‐glycosylation. A disulfide bond exists between Cys105 and Cys180, connecting the first and second extracellular loops.

Figure 4.

Proposed signal transduction pathways following NK‐1 receptor activation. Functional interaction of substance P with the NK‐1 receptor stimulates NK‐1 receptor‐mediated GDP/GTP exchange on the Gαq subunit and the subsequent activation of PLC β (phospholipase C β). The two intracellular second messengers, IP3 (inositol 1,4,5‐triphosphate) and DAG (diacylglycerol), then stimulate the mobilization of intracellular Ca2+ and the activation of PKC (protein kinase C), respectively. Current interest is focusing on the possible gene regulatory effects of G protein‐coupled receptor activation mediated by the Gβγ subunits.

Figure 5.

Immunoregulatory effects of substance P. Primary afferent C fibres containing substance P and other tachykinins are involved in the regulation of many inflammatory and immune responses. Substance P is additionally involved in the propagation of noxious stimuli from the periphery. See text for details. IL, interleukin; LTC4, leucotriene C4; OH*, hydroxyl radical; PGE, prostaglandin E and TNFα, tumour necrosis factor α. Adapted from Hartung and Tokya .



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Further Reading

Boyd ND and Leeman SE (1995) Localization of the peptide binding domain of the substance P (NK‐1) receptor using photoreactive analogues of substance P. Annals of the New York Academy of Sciences 757: 405–409.

Leeman SE and Boyd ND (1997) Substance P. In: Bittar EE and Bittar N (eds) Principles of Medical Biology: Molecular and Cellular Pharmacology, vol. 8A, pp. 133–139. Greenwich, CT: JAI Press.

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Pernow B (1983) Substance P. Pharmacological Reviews 35: 85–141.

Quartara L and Maggi CA (1997) The tachykinin NK1 receptor Part I: ligands and mechanisms of cellular activation. Neuropeptides 31: 537–563.

Quartara L and Maggi CA (1998) The tachykinin NK1 receptor Part II: distribution and pathophysiological roles. Neuropeptides 32: 1–49.

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Bremer, Andrew A, and Leeman, Susan E(Jan 2010) Substance P. In: eLS. John Wiley & Sons Ltd, Chichester. [doi: 10.1002/9780470015902.a0000206.pub2]