Role of intracellulare endothelin-converting enzyme-1 (ECE-1) as a regulator of neuropeptide function and signalling in the skin
Final Report Abstract
The sensory nervous system is ultimately involved in itch and inflammatory responses, and thus a potential target for therapy. To study the mechanisms how the sensory nervous system communicates with the immune system to control inflammation and itch (as in atopic dermatitis or prurigo nodularis) are of interest because these chronic diseases have a profound negative impact on the patient’s quality of life, and successful therapies remain an unmet medical need. Our studies showed for the first time that an intracellular neural peptidase, ECE-1, regulates neuropeptide-induced cell signaling and thereby contributes to neuro-physiological sensation, e.g. itch. We were able to show that ECE-1 was mainly contribute to receptor recycling and inhibition of ECE-1 induced sustained cell signaling. We also showed that ECE-1 inhibition induced sustained ET-1 induced itch response in mice. We were able to show that prolonged cell signaling and itch response induced by ECE-1 inhibition in vivo and in vitro is associated with a sustained ERK1/2 induction in DRG neurons, but not by p38 or PKCδ. Our murine and human data indicate that ECE-1 is an important regulator of neuropeptide-induced cell responses. In a translational setting, our ET-1 study gave evidence that ET-1, ETAR and ECE-1 are upregulated in patients with chronic pruritus suggesting a role of this pathway in human pruritic disease. The results of our studies are of interest because the role of ECE-1 in human diseases is underestimated. The identification of the role of ECE-1 for neuropeptide-induced signaling will be of interest because ECE-1 participates in the pathophysiology of neurogenic inflammation, pain and pruritus. Further, the results of our studies could be used as a basis to study the effect of different pharmaceutical inhibitors of ECE-1 for neurogenic inflammation, pain and pruritus.
Publications
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(2007) Endothelin-converting enzyme-1 regulates endosomal sorting of calcitonin receptor-like receptor and β-arrestins. JCB 175 (5): 981–997
Padilla BE, Cottrell GS, Roosterman D, Pikios S, Muller L, Steinhoff M, Bunnett NW
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Agonist-induced endocytosis of rat somatostatin receptor 1. Endocrinology 148: 1050-8 (2007)
Roosterman D., Kreuzer O.J., Brune N., Cottrell G.S., Bunnett N.W., Meyerhof W., and Steinhoff M.
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Endothelin-converting enzyme 1 degrades neuropeptides in endosomes to control receptor recycling. Proc Natl Acad Sci USA 104: 11838-43 (2007)
Roosterman D., Cottrell G.S., Padilla B.E., Muller L., Eckman C.B., Bunnett N.W., and Steinhoff M.
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(2008) Endothelin-Converting Enzyme-1 Degrades Internalized Somatostatin-14. Endocrinology 149(5):2200–2207
Roosterman D, Kempkes C, Cottrell GS, Padilla BE, Bunnett NW, Turck CW, Steinhoff M
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Intracellular degradation of somatostatin-14 following somatostatin-receptor3-mediated endocytosis in rat insulinoma cells. Febs J 275: 4728-39 (2008)
Roosterman D., Brune N.E., Kreuzer O.J., Feld M., Pauser S., Zarse K., Steinhoff M., and Meyerhof W.
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(2009). Endosomal Endothelin-converting Enzyme-1 a Regulator of ß-Arrestin-Dependent Erk Signaling. J Biol Chem 284 ( 33): 22411–22425
Cottrell GS, Padilla BE, Amadesi S, Poole DP, Murphy JE, Hardt M, Roosterman D, Steinhoff M, Bunnett NW
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(2011). Endothelin-converting enzyme-1 regulates trafficking and signalling of the neurokinin 1 receptor in endosomes of myenteric neurones. J Physiol 589.21 (2011) pp 5213–5230 5213
Pelayo JC, Poole DP, Steinhoff M, Cottrell GS and Bunnett NW
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(2011). Protein phosphatase 2A mediates resensitization of the neurokinin 1 receptor. Am J Physiol Cell Physiol. 301(4):C780-91
Murphy JE, Roosterman D, Cottrell GS, Padilla BE, Feld M, Brand E, Cedron WJ, Bunnett NW, Steinhoff M
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Clinical, cellular, and molecular aspects in the pathophysiology of rosacea. J Invest Dermatol Proc 15: 2-11 (2011)
Steinhoff M., Buddenkotte J., Aubert J., Sulk M., Novak P., Schwab V.D., Mess C., Cevikbas F., Rivier M., Carlavan I., Deret S., Rosignoli C., Metze D., Luger T.A., and Voegel J.J.
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Neurovascular and neuroimmune aspects in the pathophysiology of rosacea. J Invest Dermatol Proc 15: 53-62 (2011)
Schwab V.D., Sulk M., Seeliger S., Nowak P., Aubert J., Mess C., Rivier M., Carlavan I., Rossio P., Metze D., Buddenkotte J., Cevikbas F., Voegel J.J., and Steinhoff M.
