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

本项目对GPCR、降钙素样受体（CLR）感兴趣，该受体可被神经肽、降钙素基因相关肽（CGRP）、肾上腺髓质素（AM）和肾上腺髓质素2 （AM2）激活。这些肽已被证明有助于防止缺血性损伤。不同的信号通路可以根据肽被激活，这种现象被称为激动剂偏差。有趣的是，CLR具有额外的复杂性，因为它需要三种受体活性修饰蛋白（RAMPs）中的一种来形成受体复合物，这就产生了三种不同的功能GPCR受体。CLR和RAMP1形成CGRP亲和力最高的受体复合物，因此称为CGRP受体。AM对CLR和RAMP2复合物（称为AM1受体）具有最高的亲和力，而AM2对由CLR和RAMP2复合物组成的AM2受体具有最高的亲和力。RAMPs在信号偏置中起作用。例如，CLR和RAMP1复合物在受CGRP刺激时具有向Gas的信号偏倚，导致细胞内环AMP的升高。相反，CLR和RAMP1复合物在受AM刺激时偏向于与GaI偶联，从而抑制环AMP的产生。在CLR和RAMP2构象中观察到相反的响应。这突出了肽和RAMP在指示信号通路和生物反应中的重要性。这需要进一步了解，以开发成功的心脏药物，以减少脱靶效应和减少不必要的生理反应。

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.