skip to content

Department of Pharmacology

Clark, A

The aim of this body of work has been to further understanding of the signalling and functional properties of a unique family of cell surface receptors known as G protein-coupled receptors (GPCRs), and one of their subclasses: The CGRP receptor family. These receptors are crucial for transducing information from the extracellular to intracellular space. While much pharmacological research has gone into understanding the signalling and function of GPCRs in recombinant systems, there is a very little knowledge of these receptors in their native environment and at endogenous expression levels. Nor is there direct evidence for potentially controversial phenomena such as signalling bias in endogenous cells. This provided the impetus to address the need for a better understanding of the pharmacology of endogenous human calcitonin receptor-like receptor (CLR) in its native cellular environment. Therefore, primary human cardiovascular cells, gene editing techniques, and a host of intracellular assays were used to study the signalling properties of this GPCR family, revolving around the CLR, to attempt to uncover how these receptors function endogenously. Through the research presented here, it is shown that the CLR, when stimulated by endogenous agonists activates a whole host of signalling pathways to bring about differing physiological effects. In doing so it has revealed unique roles for calcitonin-gene related peptide (CGRP), adrenomedullin (AM), and the little-understood peptide adrenomedullin 2 (AM2). All of which are dependent on the presence of a group of GPCR accessory proteins known as receptor activity-modifying proteins (RAMPs). These proteins are not only crucial for CLR function, but this dissertation demonstrates the remarkable way in which they govern and dictate the intracellular signalling of the CGRP family of peptides endogenously. Beyond this, the G protein and accessory protein involvement in certain signalling cascades, the spatiotemporal aspects to CGRP peptide signalling, and the functional outcomes of signalling in cell organoid models are all explored. It is the author’s belief that this work adds a great deal to the understanding of the CLR, and more generally takes a step forward in the understanding of endogenous GPCR signalling bias.

Publication ID: 
Published date: 
8 February 2021 (No publication date)
Publication source: 
Publication type: 
Theses / dissertations
Journal name: 
Publication volume: 
University of Cambridge
Parent title: 
Publication number: 
Ladds, G