The role of the CGRP family of peptides in the heart; new therapies for heart disease?

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This project is interested in the GPCR, calcitonin like receptor (CLR), which can be activated by the neuropeptides, calcitonin gene-related peptide (CGRP), adrenomedullin (AM) and adrenomedullin 2 (AM2). These peptides have shown to help protect against ischaemic damage. Different signalling pathways can be activated dependent on the peptide, a phenomenon called agonist bias. Interestingly, the CLR has an added level of complexity because it requires one of three receptor activity modifying proteins (RAMPs) to form a receptor complex and this gives rise to three distinct functional GPCR receptors. CLR and RAMP1 form a receptor complex that CGRP has the highest affinity for, hence termed the CGRP receptor. AM has the highest affinity for the complex of CLR and RAMP2 (termed the AM1 receptor) and AM2 has the highest affinity for the AM2 receptor which is made up of the CLR and RAMP2 complex. The RAMPs play a role in signalling bias. For example, the CLR and RAMP1 complex when stimulated with CGRP has a signalling bias towards Gas resulting in elevation of intracellular cyclic AMP. Conversely, CLR and RAMP1 complex when stimulated with AM is biased towards coupling with GaI leading to inhibition of cyclic AMP production. In the conformation of CLR and RAMP2 the opposite response is observed. This highlights the importance of both the peptide and RAMP in dictating the signalling pathway and biological response. This needs to be understood further in order to develop successful heart drugs with far fewer off target effects and reducing undesired physiological responses.