Substance P

Abstract

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 .

close

References

Boyd ND, White CF, Cerpa R, Kaiser ET and Leeman SE (1991) Photoaffinity labeling the substance P receptor using a derivative of substance P containing p‐benzoylphenylalanine. Biochemistry 30: 336–342.

Chahl LA (2006) Tachykinins and neuropsychiatric disorders. Current Drug Targets 7: 993–1003.

Chang MM and Leeman SE (1970) Isolation of a sialogogic peptide from bovine hypothalamic tissue and its characterization as substance P. Journal of Biological Chemistry 245: 4784–4790.

Groneberg DA, Harrison S, Dinh QT et al. (2006) Tachykinins in the respiratory tract. Current Drug Targets 7: 1005–1010.

Hartung H‐P and Tokya KV (1989) Substance P, the immune system and inflammation. International Reviews of Immunology 4: 229–249.

Helke CJ, Krause JE, Mantyh PW, Couture R and Bannon MJ (1990) Diversity in mammalian tachykinin peptidergic neurons: multiple peptides, receptors, and regulatory mechanisms. FASEB Journal 4: 1606–1615.

Hershey AD and Krause JE (1990) Molecular characterization of a functional cDNA encoding the rat substance P receptor. Science 247: 958–961.

Iadorola MJ and Caudle RM (1997) Good pain, bad pain. Science 278: 239–240.

Karagiannides I, Kokkotou E, Tansky M et al. (2006) Induction of colitis causes inflammatory responses in fat depots: evidence for substance P pathways in human mesenteric preadipocytes. Proceedings of the National Academy of Sciences of the USA 103: 5207–5212.

Karagiannides I and Pothoulakis C (2009) Substance P, obesity, and gut inflammation. Current Opinion in Endocrinology, Diabetes and Obesity 16: 47–52.

Koon HW and Pothoulakis C (2006) Immunomodulatory properties of substance P: the gastrointestinal system as a model. Annals of The New York Academy of Sciences 1088: 23–40.

Lai J‐P, Lai S, Tuluc F et al. (2008) Differences in the length of the carboxyl terminus mediate functional properties of neurokinin‐1 receptor. Proceedings of the National Academy of Sciences of the USA 105: 12605–12610.

Liu D, Jiang LS and Dai LY (2007) Substance P and its receptors in bone metabolism. Neuropeptides 41: 271–283.

Macdonald SG, Dumas JJ and Boyd ND (1996) Chemical cross‐linking of the substance P (NK‐1) receptor to the alpha subunits of the G proteins Gq and G11. Biochemistry 35: 2909–2916.

Maggi CA and Schwartz TW (1997) The dual nature of the tachykinin NK1 receptor. Trends in Pharmacological Sciences 18: 351–355.

Maggio JE (1988) Tachykinins. Annual Review of Neuroscience 11: 13–28.

Nakanishi S (1986) Structure and regulation of the preprotachykinin gene. Trends in Neurosciences 9: 41–44.

Ohkubo H and Nakanishi S (1991) Molecular characterization of the three tachykinin receptors. Annals of the New York Academy of Sciences 632: 53–62.

Otsuka M and Yoshioka K (1993) Neurotransmitter functions of mammalian tachykinins. Physiological Reviews 73: 229–308.

Palma C (2006) Tachykinins and their receptors in human malignancies. Current Drug Targets 7: 1043–1052.

Reed KL, Stucchi AF, Leeman SE et al. (2008) Inhibitory effects of a neurokinin‐1 receptor antagonist on postoperative peritoneal adhesion formation. Annals of the New York Academy of Sciences 1144: 116–126.

Regoli D, Boudon A and Fauchere J‐L (1994) Receptors and antagonists for substance P and related peptides. Pharmacological Reviews 46: 551–599.

Tansky MF, Pathoulakis C and Leeman SE (2007) Functional consequences of alteration of N‐linked glycosylation sites on the neurokinin 1 receptor. Proceedings of the National Academy of Sciences of the USA 104: 10691–10696.

Von Euler US and Gaddum JH (1931) An unidentified depressor substance in certain tissue extracts. Journal of Physiology 72: 74–87.

Walsh DA and McWilliams DF (2006) Tachykinins and the cardiovascular system. Current Drug Targets 7: 1031–1042.

Yokota Y, Sasai Y, Tanaka K et al. (1989) Molecular characterization of a functional cDNA for rat substance P receptor. Journal of Biological Chemistry 264: 17649–17652.

Zhang Y, Berger A, Milne CD et al. (2006) Tachykinins in the immune system. Current Drug Targets 7: 1011–1020.

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.

Leeman SE, Aronin N and Ferris C (1982) Substance P and neurotensin. Recent Progress in Hormone Research 38: 93–132.

Nicoll RA, Schenker C and Leeman SE (1980) Substance P as a transmitter candidate. Annual Review of Neuroscience 3: 227–268.

Payan DG (1989) Neuropeptides and inflammation: the role of substance P. Annual Review of Medicine 40: 341–352.

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.

Contact Editor close
Submit a note to the editor about this article by filling in the form below.

* Required Field

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