Determining the Significance of Pathway Bias at the Calcitonin Gene-Related Peptide Receptor Family in Human Endothelial Cells (360G-Wellcome-207063_Z_17_Z)

Family B G protein coupled receptors (GPCRs), notably the calcitonin like receptor (CLR), have been implicated in cardioprotective functions. The functional GPCR is a heterodimer of CLR and one of three possible receptor activity-modifying proteins (RAMPs). There are 3 main agonists for this GPCR: calcitonin gene-related peptide (CGRP), adrenomedullin (AM), and adrenomedullin 2 (AM2). CLR is pleotropic, activating intracellular pathways through coupling to G proteins or beta-arrestins. Indeed, we recently showed, using both a heterologous yeast expression system and mammalian (HEK-293) cell lines, that the signalling bias of the CLR is dependent upon both the agonist and the RAMP. However, the cell environment of the receptor massively affects signalling bias. Therefore, to validate these results, investigation of the pharmacology of the CLR in endogenous cell lines is essential. The aim of this research is therefore to use two different human cell lines (HUVECs and HUAECs) to pharmacologically investigate CLR/RAMP2 (the adrenomedullin receptor) and CLR/RAMP1 (the CGRP receptor) when endogenously expressed. It is hoped that this will provide greater insight into the function of CLR signalling in the vascular endothelium. This information may then be used to help characterise the pathophysiology of common cardiovascular diseases such as hypertension and myocardial infarction.