The Activity of Substance P on Corneal Epithelium: Comparison
View Latest Version
Please note this is a comparison between Version 2 by Conner Chen and Version 1 by Ted Reid.

In 1931, Von Euler and Gaddum isolated substance P (SP), an undecapeptide from the tachykinin family, from equine brain and intestine tissue extracts. Numerous types of cells, including neurons, astrocytes, microglia, epithelial, and endothelial cells, as well as immune cells including T-cells, dendritic cells, and eosinophils, are responsible for its production. The corneal epithelium, immune cells, keratocytes, and neurons all express the two isoforms of NK1R, which has the highest affinity for SP. 

  • cornea
  • corneal epithelium
  • ophthalmology
  • Substance P

1. Introduction

In 1931, Von Euler and Gaddum isolated substance P (SP), an undecapeptide from the tachykinin family, from equine brain and intestine tissue extracts [1]. Numerous types of cells, including neurons, astrocytes, microglia, epithelial and endothelial cells, as well as immune cells including T-cells, dendritic cells (DCs), and eosinophils, are responsible for its production. Neurokinin 1 receptor (NK1R), Neurokinin 2 receptor (NK2R), and Neurokinin 3 receptor (NK3R) are members of the class I (rhodopsin-like) family of G-protein-coupled neurokinin receptors that SP uses to exert its biological effects [1]. The corneal epithelium, immune cells, keratocytes, and neurons all express the two isoforms of NK1R. The trigeminal ganglion ophthalmic branch fibers are primarily responsible for producing SP on the ocular surface. Healthy people’s tears have been found to contain SP and its metabolites. SP levels in tears are much lower in people with diabetic keratopathy and corneal hypoesthesia, which disturbs the homeostasis of the ocular surface. In cases of neurotrophic keratopathy, topical use of SP-derived peptide accelerates healing [1]. The most recent research supports SP’s contribution to corneal healing by encouraging epithelial cell migration and proliferation. Additionally, when applied to the eyes, SP has proinflammatory effects that result in miosis, intraocular inflammation, and conjunctival hyperemia [1].

2. Discovery of Substance P

Neuronal and non-neuronal cells generate SP, which is an 11-amino-acid-long neuropeptide that regulates tissue homeostasis, wound healing, and ocular inflammation. Substance P binds to the Neurokinin 1 receptor (NK1R), NK2R, and NK3R, which are G-protein-coupled receptors that SP binds to [2,3,4][2][3][4]. Among the receptors, NK1R has the most affinity for SP of the three. There is an abundance of data showing that SP controls immune cell activity and microbial infection immunity. Substance P was first detected in extracts from equine brain and intestine, and was found to induce transient hypotension and to facilitate muscle contraction in the intestine when injected intravenously into anesthetized rabbits. The sequence of SP remained elusive until Leeman and coworkers discovered a peptide that stimulated salivary secretion when injected into anesthetized rats while attempting to isolate corticotropin-releasing factor [5]. This peptide was referred to as sialogen until its physical and chemical characteristics were compared to those of SP. It was later found to be identical to SP. Further purification led to the sequence of SP, reported in 1971 by Chang, Leeman, and Niall: Arg-Pro-Lys-Pro-Gln-Gln-Phe-Phe-Gly-Leu-Met-NH2. Substance P belongs to a family of peptides known as tachykinins. There have been five mammalian tachykinins identified thus far: Substance P, neurokinin A (NKA), neurokinin B (NKB), neuropeptide K (NPK), and neuropeptide Y (NPY). Tachykinins have a common carboxy-terminal sequence Phe-X-Gly-Leu-Met-NH2, where X is an aliphatic or aromatic amino acid [6,7][6][7].

3. Molecular Biology of Substance P

The nucleic acid sequences for SP, NKA, NPK, and NPY are encoded on a single gene, while the gene encoding NKB lies in a separate location [8,9,10][8][9][10]. The gene containing the SP sequence is approximately eight kilobases in length and contains seven exons [11]. The transcribed SP encoding gene undergoes alternative splicing to produce three distinct preprotachykinin (PPT) mRNA’s that are designated as a-, P- and y-PPT mRNA [11]. A fourth PPT mRNA, 6, has been identified in rats [12]. Even though all PPT mRNA’s contain the SP sequence, the mRNAs are subject to differential exon usage. Interestingly, differences in the splicing patterns seem to be tissue-specific [13,14][13][14]. In the adult rat, y-PPT mRNA is the most abundant of the three PPT mRNAs. However, in bovines, different PPT mRNAs are more prevalent in different tissues. The exact mechanism for determining differential mRNA splicing is unknown, but the formation of secondary structures in the RNA may be important [15]. These PPT mRNAs, once translated, undergo post-translational processing to form the desired tachykinins.

4. Vasoactive Effects of Substance P

The systemic hypotensive effect of SP was one of its defining characteristics and has been shown to result from peripheral vasodilation. When endothelial cells are subjected to physiological changes, such as hypoxia or shear stress, SP is released from these cells [16,17,18,19][16][17][18][19]. Nitric oxide (NO) has been shown to mediate the SP-induced relaxation of porcine coronary arterioles [20]. Jin et al. demonstrated that SP induces vasoactive intestinal peptide (VIP) release and NO production [20,21][20][21]. Other results obtained by Sharma and Davis suggest that in porcine coronary artery endothelial cells, SP induces a rise in intracellular Ca2+. The resulting increase in calcium activates an intermediate-conductance Ca2+-activated K+ channel, which produces hyperpolarization. This ultimately produces a sustained Ca2+ entry, which is necessary for endothelium-derived nitric oxide production. SP has also been shown to have profound effects on vasomotion, where a regular, fluctuating flow pattern in skeletal muscles was seen after intravenous injections [22]. In addition, SP causes aggregation of leukocytes and platelets [23]. The effect of SP on vasodilation, vasomotion, leukocytes, and platelets indicates a complex role for this peptide in response to tissue trauma. SP causes a process called neurogenic inflammation, the vasodilation and plasma extravasation that occurs following the release of SP from capsaicin-sensitive nerves [24]. This process was shown to be mediated by the NKl receptor by direct measurement of protein release from blood vessels [24]. Substance P, released by proinflammatory stimuli, causes plasma protein extravasation by increasing endothelial permeability, indicating a potential role for SP in the inflammatory process. The SP antagonist CP-96,345 was shown to block Evans blue dye leakage, a measure of plasma protein extravasation, induced by SP and releasers of endogenous SP [25]. This result indicates that SP controls endothelial permeability by binding at the NKl receptor. Recently SP was also found to cause altered vascular permeability in diabetic rats [26].

5. Secretory Effects of Substance P

Substance P may help regulate the release of anterior pituitary hormones. Substance P applied intracerebroventricularly in rats inhibits the release of growth hormone, but increases levels of plasma prolactin [27,28,29][27][28][29]. Intrathecally applied SP in rats stimulated the release of epinephrine and norepinephrine [30,31][30][31]. It has also been suggested that SP interacts with the release of opioid peptides into the circulatory system [32]. In addition, SP has been shown to increase parotid gland secretion through an inositol trisphosphate (IP3)-mediated mechanism, where its effects were measured by the release of labeled protein [33]. Measuring amylase release from dispersed acinar cells has also shown that SP stimulates pancreatic secretion [34]. In the gastrointestinal tract, SP induces secretion of pepsinogen in dogs and inhibition of gastric acid section [35,36][35][36]. Contradictory information on insulin and glucagon secretion stems from the fact that SP stimulates the release of these two substances in dogs, but has an inhibitory effect on these substances in rats [37,38][37][38]. Substance P also induces histamine release by human mast cells and causes eosinophil cationic protein release by human eosinophils [39,40][39][40].

6. Mitogenic Effects of Substance P

A new and intriguing development is the discovery that regulatory peptides can also act as mitogens for cells in culture. A direct growth-promoting effect of SP and substance K (NKA) has been reported in smooth muscle cells and human skin fibroblasts [41,42,43,44][41][42][43][44]. Substance P also enhances the proliferation of human blood T-lymphocytes by specific receptors for this peptide [41]. Substance P was also reported to stimulate release of PGE2 and proliferation in rheumatoid synoviocytes, and to stimulate neovascularization [44,45][44][45]. Recently, Reid et al. showed that SP at picomolar levels is mitogenic for ocular epithelial cells. These findings are in accord with other evidence which indirectly suggests that tachykinins released by sensory nerves in the skin, joints, and other peripheral tissues may function as mediators of local inflammatory and wound healing responses [46]. It is interesting to note that SP stimulates mitogenesis of embryonic rat aorta cells, but fails to induce significant contraction of these cells. In contrast, SP induced contraction of cultured adult rat vascular smooth muscle cells, but failed to stimulate mitogenesis [47]. Thus, the differentiation state of the cell modulates the mode of action of SP. Substance P may interact with the immune system by partaking in the regulation of lymphocytes. Concentrations in the nanomolar range are capable of stimulating human and mouse lymphocyte proliferation [41]. Substance P has been proposed to be involved in the regulation of glial cell response to injury in the central nervous system [48].

References

  1. Singh, R.B.; Naderi, A.; Cho, W.; Ortiz, G.; Musayeva, A.; Dohlman, T.H.; Chen, Y.; Ferrari, G.; Dana, R. Modulating the tachykinin: Role of substance P and neurokinin receptor expression in ocular surface disorders. Ocul. Surf. 2022, 25, 142–153.
  2. Suvas, S. Role of Substance P Neuropeptide in Inflammation, Wound Healing, and Tissue Homeostasis. J. Immunol. 2017, 199, 1543–1552.
  3. Maggi, C.A.; Patacchini, R.; Rovero, P.; Giachetti, A. Tachykinin receptors and tachykinin receptor antagonists. J. Auton. Pharmacol. 1993, 13, 23–93.
  4. Steinhoff, M.S.; von Mentzer, B.; Geppetti, P.; Pothoulakis, C.; Bunnett, N.W. Tachykinins and their receptors: Contributions to physiological control and the mechanisms of disease. Physiol. Rev. 2014, 94, 265–301.
  5. Chang, M.M.; Leeman, S.E. Isolation of a Sialogogic Peptide from Bovine Hypothalamic Tissue and Its Characterization as Substance P. J. Biol. Chem. 1970, 245, 4784–4790.
  6. Stone, R.A.; Kuwayama, Y.; Laties, A.M. Regulatory peptides in the eye. Experientia 1987, 43, 791–800.
  7. Euler, U.S.V.; Gaddum, J.H. An unidentified depressor substance in certain tissue extracts. J. Physiol. 1931, 72, 74–87.
  8. Nawa, H.; Kotani, H.; Nakanishi, S. Tissue-specific generation of two preprotachykinin mRNAs from one gene by alternative RNA splicing. Nature 1984, 312, 729–734.
  9. Krause, J.E.; Blount, P.; Sachais, B.S. Molecular Biology of Receptors. In The Tachykinin Receptors; Humana Press: Totowa, NJ, USA, 1994; pp. 165–218.
  10. Kotani, H.; Hoshimaru, M.; Nawa, H.; Nakanishi, S. Structure and gene organization of bovine neuromedin K precursor. Proc. Natl. Acad. Sci. USA 1986, 83, 7074–7078.
  11. Carter, M.S.; Krause, J.E. Structure, expression, and some regulatory mechanisms of the rat preprotachykinin gene encoding substance P, neurokinin A, neuropeptide K, and neuropeptide gamma. J. Neurosci. 1990, 10, 2203–2214.
  12. Harmar, A.J.; Hyde, V.; Chapman, K. Identification and cDNA sequence of δ-preprotachykinin, a fourth splicing variant of the rat substance P precursor. FEBS Lett. 1990, 275, 22–24.
  13. Krause, J.E.; Chirgwin, J.M.; Carter, M.S.; Xu, Z.S.; Hershey, A.D. Three rat preprotachykinin mRNAs encode the neuropeptides substance P and neurokinin A. Proc. Natl. Acad. Sci. USA 1987, 84, 881–885.
  14. Krause, J.E.; Cremins, J.D.; Carter, M.S.; Brown, E.R.; MacDonald, M.R. Solution hybridization-nuclease protection assays for sensitive detection of differentially spliced substance P- and neurokinin A-encoding messenger ribonucleic acids. In Methods Enzymology; Elsevier: Amsterdam, The Netherlands, 1989; pp. 634–652.
  15. Krause, J.E.; Bu, J.Y.; Takeda, Y.; Blount, P.; Raddatz, R.; Sachais, B.S.; Chou, K.B.; Takeda, J.; McCarson, K.; DiMaggio, D. Structure, expression and second messenger-mediated regulation of the human and rat substance P receptors and their genes. Regul. Pept. 1993, 46, 59–66.
  16. Nowicki, M.; Ostalska-Nowicka, D.; Kondraciuk, B.; Miskowiak, B. The significance of substance P in physiological and malignant haematopoiesis. J. Clin. Pathol. 2007, 60, 749–755.
  17. Bény, J.L. Effect of substance P on the membrane potential of coronary arterial endothelial cellsin situ. Agents Actions 1990, 31, 317–320.
  18. Milner, P.; Ralevic, V.; Hopwood, A.M.; Fehér, E.; Lincoln, J.; Kirkpatrick, K.A.; Burnstock, G. Ultrastructural localisation of substance P and choline acetyltransferase in endothelial cells of rat coronary artery and release of substance P and acetylcholine during hypoxia. Experientia 1989, 45, 121–125.
  19. Ralevic, V.; Milner, P.; Hudlická, O.; Kristek, F.; Burnstock, G. Substance P is released from the endothelium of normal and capsaicin-treated rat hind-limb vasculature, in vivo, by increased flow. Circ. Res. 1990, 66, 1178–1183.
  20. Kuo, L.; Chilian, W.M.; Davis, M.J. Interaction of pressure- and flow-induced responses in porcine coronary resistance vessels. Am. J. Physiol.-Heart Circ. Physiol. 1991, 261, H1706–H1715.
  21. Jin, J.G.; Misra, S.; Grider, J.R.; Makhlouf, G.M. Functional difference between SP and NKA: Relaxation of gastric muscle by SP is mediated by VIP and NO. Am. J. Physiol.-Gastrointest. Liver Physiol. 1993, 264, G678–G685.
  22. Sandberg, B.E.B.; Iversen, L.L. Substance P. J. Med. Chem. 1982, 25, 1009–1015.
  23. Öhlén, A.; Thureson-Klein, Å.; Lindbom, L.; Persson, M.G.; Hedqvist, P. Substance P Activates Leukocytes and Platelets in Rabbit Microvessels. J. Vasc. Res. 1989, 26, 84–94.
  24. White, D.M.; Helme, R.D. Release of substance P from peripheral nerve terminals following electrical stimulation of the sciatic nerve. Brain Res. 1985, 336, 27–31.
  25. Lembeck, F.; Donnerer, J.; Tsuchiya, M.; Nagahisa, A. The non-peptide tachykinin antagonist, CP-96,345, is a potent inhibitor of neurogenic inflammation. Br. J. Pharmacol. 1992, 105, 527–530.
  26. Mathison, R.; Davison, J.S. Altered vascular permeability responses to substance P in diabetic rats: Interactions with a nitric oxide synthesis inhibitor. Eur. J. Pharmacol. 1993, 240, 163–168.
  27. Arisawa, M.; Snyder, G.D.; De Palatis, L.; Ho, R.H.; Xu, R.K.; Pan, G.; McCann, S.M. Role of substance P in suppressing growth hormone release in the rat. Proc. Natl. Acad. Sci. USA 1989, 86, 7290–7294.
  28. Chihara, K.; Arimura, A.; Coy, D.H.; Schally, A.V. Studies on the Interaction of Endorphins, Substance P, and Endogenous Somatostatin in Growth Hormone and Prolactin Release in Rats. Endocrinology 1978, 102, 281–290.
  29. Eckstein, N.; Wehrenberg, W.B.; Louis, K.; Carmel, P.W.; Zimmermann, E.A.; Frantz, A.G.; Ferin, M. Effects of Substance P on Anterior Pituitary Secretion in the Female Rhesus Monkey. Neuroendocrinology 1980, 31, 338–342.
  30. Hasséssian, H.; Couture, R.; de Champlain, J. Sympathoadrenal Mechanisms Underlying Cardiovascular Responses to Intrathecal Substance P in Conscious Rats. J. Cardiovasc. Pharmacol. 1990, 15, 736–744.
  31. Yashpal, K.; Gauthier, S.G.; Henry, J.L. Substance P given intrathecally at the spinal T9 level increases adrenal output of adrenaline and noradrenaline in the rat. Neuroscience 1985, 15, 529–536.
  32. Cridland, R.A.; Henry, J.L. An adrenal-mediated, naloxone-reversible increase in reaction time in the tail-flick test following intrathecal administration of substance p at the lower thoracic spinal level in the rat. Neuroscience 1988, 26, 243–251.
  33. Dreux, C.; Imhoff, V.; Mauduit, P.; Rossignol, B. Substance P Effect on the Secretory Process in Rat Parotid Gland. In Substance P and Neurokinins; Springer: New York, NY, USA, 1987; pp. 195–196.
  34. Gardner, J.D.; Jackson, M.J. Regulation of amylase release from dispersed pancreatic acinar cells. J. Physiol. 1977, 270, 439–454.
  35. Vigna, S.R.; Mantyh, C.R.; Soll, A.H.; Maggio, J.E.; Mantyh, P.W. Substance P receptors on canine chief cells: Localization, characterization, and function. J. Neurosci. 1989, 9, 2878–2886.
  36. Yokotani, K.; Fujiwara, M. Effects of substance-P(SP) on parasympathetically stimulated gastric acid secretion and mucosal blood flow(MBF) in rats. Jpn. J. Pharmacol. 1984, 36, 250.
  37. Chiba, K.; Kontani, K.; Tadenuma, H.; Katada, T.; Hoshi, M. Induction of starfish oocyte maturation by the beta gamma subunit of starfish G protein and possible existence of the subsequent effector in cytoplasm. Mol. Biol. Cell 1993, 4, 1027–1034.
  38. Kaneto, A.; Kaneko, T.; Kajinuma, H.; Kosaka, K. Effects of Substance P and Neurotensin Infused Intrapancreatically on Glucagon and Insulin Secretion. Endocrinology 1978, 102, 393–401.
  39. Church, M.K.; Lowman, M.A.; Robinson, C.; Holgate, S.T.; Benyon, C. Interaction of Neuropeptides with Human Mast Cells. Int. Arch. Allergy Immunol. 1989, 88, 70–78.
  40. Iwamoto, I.; Nakagawa, N.; Yamazaki, H.; Kimura, A.; Tomioka, H.; Yoshida, S. Mechanism for substance P-induced activation of human neutrophils and eosinophils. Regul. Pept. 1993, 46, 228–230.
  41. Payan, D.G.; Brewster, D.R.; Missirian-Bastian, A.; Goetzl, E.J. Substance P recognition by a subset of human T lymphocytes. J. Clin. Investig. 1984, 74, 1532–1539.
  42. Nilsson, K.O. Improved final height in girls with Turner’s syndrome treated with growth hormone and oxandrolone. J. Clin. Endocrinol. Metab. 1996, 81, 635–640.
  43. Nilsson, J.; von Euler, A.M.; Dalsgaard, C.-J. Stimulation of connective tissue cell growth by substance P and substance K. Nature 1985, 315, 61–63.
  44. Ziche, M.; Morbidelli, L.; Pacini, M.; Dolara, P.; Maggi, C.A. NK1-receptors mediate the proliferative response of human fibroblasts to tachykinins. Br. J. Pharm. 1990, 100, 11–14.
  45. Lotz, M.; Vaughan, J.H.; Carson, D.A. Effect of Neuropeptides on Production of Inflammatory Cytokines by Human Monocytes. Science 1988, 241, 1218–1221.
  46. Lotz, M.; Carson, D.A.; Vaughan, J.H. Substance P Activation of Rheumatoid Synoviocytes: Neural Pathway in Pathogenesis of Arthritis. Science 1987, 235, 893–895.
  47. Mitsuhashi, M.; Payan, D.G. The mitogenic effects of vasoactive neuropeptides on cultured smooth muscle cell lines. Life Sci. 1987, 40, 853–861.
  48. Matthews, M.R.; Connaughton, M.; Cuello, A.C. Ultrastructure and distribution of substance P-immunoreactive sensory collaterals in the guinea pig prevertebral sympathetic ganglia. J. Comp. Neurol. 1987, 258, 28–51.
More
© Text is available under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/)
ScholarVision Creations
Feedback