Graeme Cottrell

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

My interest in peptidases and proteolytic processes started during my Ph.D. at the University of Leeds. When I moved to the University of California, San Francisco, to work as post-doctoral fellow I then became interested in the physiological and pathophysiological roles of proteolysis. Protease-activated receptors (PARs) are a sub-family of G protein-coupled receptors (GPCRs) that are activated by the proteolytic action of certain peptidases. I was the first to show that trypsin IV was co-expressed with PAR₂ in epithelial cells of the prostate, colon, and airway and in human colonic mucosa and can signal to these cells by cleaving PAR₂1. Trypsin IV is an inhibitor-resistant form of trypsin, and can signal through PARs, even in the presence of inhibitors and thus, may contribute to the sustained signaling that may lead to disease. We also discovered that peptidases such as trypsin IV can signal to neurons through PAR₁ and PAR₂ to induce pain and neurogenic inflammation and that certain proteases are upregulated during states of intestinal inflammation2^,3 . We have also evaluated the contributions of peptidases and PARs to inflammation and pain transmission. In particular we have highlighted the molecular process by which PAR₂ sensitize transient receptor potential channels (TRPs) to mediate nociception and neurogenic inflammation, through the release of neuropeptides4^,5 .

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.

Recently my research has focused on proteolytic processes in endosomes. We discovered a new role for endothelin-converting enzyme-1. This endosomal peptidase, by degrading and altering agonist availability in endosomes, regulates the recycling of the neurokinin 1 receptor and calcitonin receptor-like receptor, the receptors for substance P (SP) and calcitonin gene-related peptide (CGRP), respectively. This mechanism resensitizes the pro-inflammatory effects of SP in vivo7^,8 and promotes the resensitization of responses to CGRP in mesenteric arteries9. We also discovered that agonist availability in endosomes has profound effects on SP-induced mitogenic signaling from endosomes. We observed that endosomal proteolysis attenuates SP-induced mitogenic signaling in the nucleus to prevent cell death10. Thus, as endosomal proteolysis regulates the presence of GPCRs at the cell-surface (which is required for signaling) and the signaling of internalized GPCRs, targeting endosomal peptidases may represent a novel target for the treatment of peptide driven diseases.

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.