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Graeme Cottrell

dr graeme cottrell portrait
  • School Director of Postgraduate Research Studies

Areas of interest

My research is focused on understanding the role of peptidases and neuropeptides in the trafficking and signaling of receptors and ion channels expressed in the cardiovascular and nervous systems. The objective is to understand the molecular and cellular basis of mechanisms that regulate the signal transduction evoked by cell-surface receptors and ion channels and how dysregulation of these mechanisms can lead to pathological conditions and cause disease.

Proteolysis and Disease

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Regulation of GPCR trafficking

Another of my research interests is to elucidate how peptidases and neuropeptides regulate the trafficking and signaling of GPCRs. For example, we showed that following activation, PAR2 is covalently modified by the addition of ubiquitin molecules to intracellular lysines residues. This modification directs the cellular machinery to traffic the receptor from the cell-surface, through the endosomal system to be degraded by peptidases in the lysosome, where signal transduction is irrevocably terminated6.

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Current Research

My current work is focused on understanding the role of the neuropeptides adrenomedullin (ADM) and CGRP in the trafficking and signaling of their receptors in the vascular and nervous systems. ADM and CGRP share multiple effects in the cardiovascular system, where they cause vasorelaxation and endothelial cell proliferation. In the nervous system both ADM and CGRP are important in the transmission of pain. ADM and CGRP and their receptors contribute to the pathophysiology of migraine, hypertension, ischemic heart disease, and cardiac and renal failure. Currently, CGRP receptor antagonists are in clinical trials for the treatment of migraine.

My work is also directed to understand the interplay between peptidases, PARs and TRPs in the development of inflammation and pain processes. We have previously shown that agonists of PAR2 sensitize TRPV1 and TRPV4 to contribute to inflammation and the sensation of pain. My laboratory aims to expand our knowledge of the basic molecular mechanisms that regulate peptidases, neuropeptides, GPCRs and TRPs. This is essential for understanding how vascular and nervous systems are regulated and will permit the development of novel therapies to treat human disease.

Selected publications

References

1. Cottrell, G. S., Amadesi, S., Grady, E. F. & Bunnett, N. W. Trypsin IV, a novel agonist of protease-activated receptors 2 and 4. J Biol Chem 279, 13532-13539, (2004).

2. Knecht, W., Cottrell, G. S., Amadesi, S., Mohlin, J., Skaregarde, A., Gedda, K., Peterson, A., Chapman, K., Hollenberg, M. D., Vergnolle, N. & Bunnett, N. W. Trypsin IV or mesotrypsin and p23 cleave protease-activated receptors 1 and 2 to induce inflammation and hyperalgesia. J Biol Chem 282, 26089-26100, (2007).

3. Cottrell, G. S., Amadesi, S., Pikios, S., Camerer, E., Willardsen, J. A., Murphy, B. R., Caughey, G. H., Wolters, P. J., Coughlin, S. R., Peterson, A., Knecht, W., Pothoulakis, C., Bunnett, N. W. & Grady, E. F. Protease-activated receptor 2, dipeptidyl peptidase I, and proteases mediate Clostridium difficile toxin A enteritis. Gastroenterology 132, 2422-2437, (2007).

4. Grant, A. D., Cottrell, G. S., Amadesi, S., Trevisani, M., Nicoletti, P., Materazzi, S., Altier, C., Cenac, N., Zamponi, G. W., Bautista-Cruz, F., Lopez, C. B., Joseph, E. K., Levine, J. D., Liedtke, W., Vanner, S., Vergnolle, N., Geppetti, P. & Bunnett, N. W. Protease-activated receptor 2 sensitizes the transient receptor potential vanilloid 4 ion channel to cause mechanical hyperalgesia in mice. J Physiol 578, 715-733, (2007).

5. Amadesi, S., Nie, J., Vergnolle, N., Cottrell, G. S., Grady, E. F., Trevisani, M., Manni, C., Geppetti, P., McRoberts, J. A., Ennes, H., Davis, J. B., Mayer, E. A. & Bunnett, N. W. Protease-activated receptor 2 sensitizes the capsaicin receptor transient receptor potential vanilloid receptor 1 to induce hyperalgesia. J Neurosci 24, 4300-4312, (2004).

6. Jacob, C., Cottrell, G. S., Gehringer, D., Schmidlin, F., Grady, E. F. & Bunnett, N. W. c-Cbl mediates ubiquitination, degradation, and down-regulation of human protease-activated receptor 2. J Biol Chem 280, 16076-16087, (2005).

7. Cattaruzza, F., Cottrell, G. S., Vaksman, N. & Bunnett, N. W. Endothelin-converting enzyme 1 promotes re-sensitization of neurokinin 1 receptor-dependent neurogenic inflammation. Br J Pharmacol 156, 730-739, (2009).

8. Roosterman, D., Cottrell, G. S., Padilla, B. E., Muller, L., Eckman, C. B., Bunnett, N. W. & Steinhoff, M. Endothelin-converting enzyme 1 degrades neuropeptides in endosomes to control receptor recycling. Proc Natl Acad Sci U S A 104, 11838-11843, (2007).

9. McNeish, A. J., Roux, B. T., Aylett, S-B., Van Den Brink, A. M. & Cottrell, G. S. Endosomal proteolysis regulates calcitonin gene-related peptide responses in mesenteric arteries. Br J Pharmacol 167, 1679-1690, (2012). 

10. Cottrell, G. S., Padilla, B. E., Amadesi, S., Poole, D. P., Murphy, J. E., Hardt, M., Roosterman, D., Steinhoff, M. & Bunnett, N. W. Endosomal endothelin-converting enzyme-1: a regulator of beta-arrestin-dependent ERK signaling. J Biol Chem 284, 22411-22425, 2009).

Publications

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