Substance P, Analogs and Fragments

Definition
Substance P (SP) an undecapeptide, is abundant both in the periphery and in the CNS, where it is usually co-localised with one of the classical neurotransmitters, most commonly serotonin (5- HT) 1.

Related Peptides
SP belongs to a family of neuropeptides known as tachykinins that share the common C-terminal sequence: Phe-X-Gly-Leu-Met-NH2. The three most common tachykinins are SP, neurokinin A (NKA), and neurokinin B (NKB); their biologic actions are mediated through specific cell-surface receptors designated NK1, NK2, and NK3, with SP the preferred agonist for NK1 receptors, NKA for NK2 receptors, and NKB for NK3 receptors 2.

Discovery
SP was originally discovered in 1931 by von Euler and Gaddum as a tissue extract that caused intestinal contraction in vitro; its biologic actions and tissue distribution were further investigated over subsequent decades 3.

Structural Characteristics
SP is an 11-residue neuropeptide with the sequence Arg-Pro-Lys-Pro-Gln-Glin-Phe-Gly-Leu-Met-NH2) 4. In a study, the C- and N-terminal fragments of SP were compared to the parent molecule with respect to their ability to: (a) contract the isolated guinea pig ileum, (b) induce salivation in the rat, (c) excite single cat dorsal horn neurones, and (d) induce scratching by intracranial injections in mice. C-terminal fragments as small as the heptapeptide were potent SP agonists on all assay systems. C-terminal fragments containing five amino acids or less were, at most, only weakly active. N-terminal fragments were totally inactive on the isolated guinea pig ileum. On the rat salivation and central nervous system assays, however, N-terminal fragments were capable of weak SP-like activity 5. The results obtained, indicated that while the carboxy terminal of SP is essential for peptide bronchoactivity, loss of amino terminal peptides (up to four residues) actually enhances bronchoconstrictor responses to the peptide. Part of this enhancement appears to result from differences in the enzymatic degradation of SP and SP5-11. The data suggest that cleavage of SP by dipeptidyl aminopeptidases could enhance its bioactivity 6. SP analogs: Senktide (succinyl-[Asp6,Me-Phe8]SP-(6-11)), a selective analog for the NK-3 (SP-N) receptor, is 20-100 times more potent than SP and about 1000-fold more potent than the selective analogs for the NK-1 (SP-P) receptor, which resides on muscle cells 7. Effects of five SP analogs on the licking, biting and scratching response induced by neurokinin (NK) 1 receptor agonists such as SP, physalaemin and (p-Glu6,Pro9)-SP (6-11) (septide) were studied after intrathecal injections in mice. Peptide brought about a SP-like behavioral response, and was approximately 25 times more potent than the D-Pro9 analog, D-septide. Septide-induced response was significantly reduced by lower doses of (D-Arg1, D-Pro2,4, D-Phe7, D-His9, Leu11)-SP than (D- Phe7, D-His9, Leu11)-SP (6-11). In contrast, (D-Arg1, D-Pro2,4, D-Phe7, D-His9)-SP (0.5-1.0 nmol) and (D-Phe7, D-His9)-SP (6-11) (0.5-2.0 nmol) inhibited only SP-induced behavioral response, but not physalaemin- or septide-induced response. The results of this study indicate that NK-1 receptor agonists are not necessarily affected to a same degree by SP analogs containing D-His 8. Analogues of substance P, [D-Arg1,D-Phe5,D-Trp7,9,Leu11] SP (SpD) and [Arg6,D-Trp7,9,NmePhe8]substance P can inhibit neuropeptide-stimulated Ca2+ mobilization, tyrosine phosphorylation, and ERK activation . Crucially, SpD and [Arg6,D-Trp7,9,NmePhe8] SP inhibit SCLC cell growth in vivo and in vitro and stimulate SCLC cell apoptosis. SP analogues were characterized originally as "broad spectrum neuropeptide antagonists" 9.

Mode of Action
The SP receptor is a G protein-coupled receptor, in many respects similar to other well-studied receptors in psychiatry, particularly monoamine receptors 2. The interaction of SP with its receptor activates Gq, which in turn activates phospholipase C to break down phosphatidyl inositol bisphosphate into inositol trisphosphate (IP3) and diacylglycerol (DAG). IP3 acts on specific receptors in the sarcoplasmic reticulum to release intracellular stores of Ca2+, while DAG acts via protein kinase C to open L-type calcium channels in the plasma membrane. The rise in intracellular [Ca2+] induces the tissue response. With an array of actions as diverse as that seen with SP, there is scope for numerous therapeutic possibilities 10.

Functions
In the central nervous system, SP is associated with the regulation of mood disorders, anxiety, stress, reinforcement, neurogenesis, neurotoxicity and pain. In the digestive tract, SP, along with some other tachykinins, are neurotransmitters that regulate motor activity, secretion of ions and fluid, as well as vascular functions 11, 12.

References
1. Argyropoulos SV, Nutt DJ (2000). Substance P antagonists: novel agents in the treatment of depression. Expert Opin Investig Drugs, 9(8):1871-1875.
2. Book: Substance P and Related Tachykinins. Chapter 13: Neuropsychopharmacology: By Nadia MJ, Kramer MS.
3. Senba E, Tohyama M (1985). Origin and fine structure of substance P-containing nerve terminals in the facial nucleus of the rat:an immunohistochemical study. Exp Brain Res., 57(3):537-546.
4. Seidel MF, Tsalik J, Vetter H, Müller W (2007). Substance P in Rheumatic Diseases. Current Rheumatology Reviews, 3:17-30.
5. Piercey MF, Dobry PJ, Einspahr FJ, Schroeder LA, Masiques N (1982) Use of substance P fragments to differentiate substance P receptors of different tissues. Regulatory Peptides, 3(5-6):337-349.
6. Shore SA, Drazen JM (1988). Airway responses to substance P and substance P fragments in the guinea pig. Pulm Pharmacol., 1(3):113-118.
7. Hanani M, Chorev M, Gilon C, Selinger Z (1988). The actions of receptor-selective substance P analogs on myenteric neurons: an electrophysiological investigation. European journal of pharmacology, 153(2-3):247-253.
8. Sakurada T, Yamada T, Tan-no K, Manome Y, Sakurada S, Kisara K, Ohba M (1991). Differential effects of substance P analogs on neurokinin 1 receptor agonists in the mouse spinal cord. J Pharmacol Exp Ther., 259:205-210
9. MacKinnon AC, Waters C, Jodrell D, Haslett C, Sethi T (2001). Bombesin and Substance P Analogues Differentially Regulate G-protein Coupling to the Bombesin Receptor. J. Biol. Chem., 276(30):28083-28091..
10. Khawaja AM, Rogers DF (1996). Tachykinins: receptor to effector. Int J Biochem Cell Biol., 28(7):721-738.
11. Leeman SE, Mroz EA (1974). Substance P. Life Sci., 15(12):2033–2044.
12. Wiesenfeld-Hallin Z, Xu XJ (1993). The differential roles of substance P and neurokinin A in spinal cord hyperexcitability and neurogenic inflammation. Regul Pept., 46(1-2):165-173

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