What is the mechanism of Calcitonin Gene-Related Peptide (CGRP) receptors?

From the Guidelines

CGRP receptors function through a complex signaling mechanism that mediates pain and inflammatory responses, and the most recent evidence suggests that blocking the CGRP receptor or binding to the CGRP peptide itself can prevent this signaling cascade and reduce migraine symptoms. These receptors are composed of calcitonin receptor-like receptor (CLR) and receptor activity-modifying protein 1 (RAMP1), forming a functional heterodimer. When calcitonin gene-related peptide (CGRP) binds to this receptor complex, it activates adenylyl cyclase via G-protein coupling, leading to increased intracellular cAMP levels. This triggers downstream signaling cascades including protein kinase A activation, which ultimately results in vasodilation, neurogenic inflammation, and pain sensitization. The receptor mechanism involves conformational changes upon CGRP binding that facilitate G-protein interaction and signal transduction. This pathway is particularly important in migraine pathophysiology, where CGRP release from trigeminal nerve endings causes vasodilation and neurogenic inflammation. Modern migraine treatments like monoclonal antibodies (erenumab, fremanezumab, galcanezumab) and gepants (ubrogepant, rimegepant) work by either blocking the CGRP receptor or binding to the CGRP peptide itself, preventing this signaling cascade and reducing migraine symptoms, as supported by recent studies 1.

Some key points to consider:

• CGRP receptors play a crucial role in mediating pain and inflammatory responses
• Blocking the CGRP receptor or binding to the CGRP peptide itself can prevent the signaling cascade and reduce migraine symptoms
• Modern migraine treatments like monoclonal antibodies and gepants work by targeting the CGRP pathway
• The most recent evidence supports the use of these treatments for migraine prevention and acute treatment, as seen in studies 1
• The receptor mechanism involves conformational changes upon CGRP binding that facilitate G-protein interaction and signal transduction
• This pathway is particularly important in migraine pathophysiology, where CGRP release from trigeminal nerve endings causes vasodilation and neurogenic inflammation.

From the Research

CGRP Receptors Mechanism

• The CGRP receptor is a complex of calcitonin receptor-like receptor (CLR) and receptor activity-modifying protein 1 (RAMP1) 2
• The CGRP receptor activates many of the same signalling pathways common for other GPCRs, including the family of G proteins and a variety of protein kinases and transcription factors 2
• The CGRP receptor also activates distinct signalling pathways as the receptor is trafficking along the endocytic conduit 2
• CGRP is capable of activating multiple receptors and could have more than one endogenous receptor 3
• The recent identification of the CGRP-responsive calcitonin receptor/RAMP1 complex (AMY1 receptor - amylin subtype 1 receptor) in the trigeminovascular system warrants a deeper consideration of the molecular identity of CGRP receptor(s) involved in the pathophysiology, and thus potential treatment of migraine 3

Signalling Pathways

• The CGRP receptor elicits diverse signalling cascades in model cell lines 2
• CGRP-mediated signalling pathways in primary cells pertinent to migraine include neurons, glial cells, and vascular smooth muscle cells 2
• Investigation of all the CGRP- and CGRP receptor-mediated signalling cascades is vital if we are to fully understand CGRP's role in migraine and will no doubt unearth new targets for the treatment of migraine and other CGRP-driven diseases 2

CGRP Receptor Components

• The CGRP receptor components include the calcitonin receptor-like receptor (CLR) and receptor activity-modifying protein 1 (RAMP1) 2
• The molecular mechanisms controlling the internalization and post-endocytic trafficking (recycling and degradation) of the CGRP receptor are complex and involve multiple signalling pathways 2

Therapeutic Targets

• CGRP and its receptors are obvious druggable targets for novel anti-migraine agents 4
• Anti-CGRP and anti-CGRP receptor monoclonal antibodies have been developed as preventive and acute treatments for migraine 5, 4
• The potential risks of a long-term inhibition of CGRP functions have raised concerns, but evidence exists that plasma CGRP is detectable in patients chronically treated with anti-CGRP mABs, which might represent a potential advantage in the safety profile of anti-CGRP mABs 4