Calcitonin gene related peptide receptor

The calcitonin gene-related peptide receptor is a membrane-bound receptor protein found in vertebrates that is activated by its ligand, the calcitonin gene-related peptide (CGRP). The receptor mediates its effects via activation of Gs proteins and subsequent activation of adenylyl cyclases. The coding gene (CALCRL) for the calcitonin receptor-like receptor is located on chromosome 2 in gene locus q31-q32.

All peptides of the calcitonin peptide group act via one of 2 G-protein-coupled receptors (GPCR), the calcitonin receptor (CTR) or the calcitonin gene-related peptide receptor.

Heterodimerization of these GPCRs with one of three receptor activity-modifying proteins (RAMP) is increased. The complex formation of several proteins is crucial for the ligand specificity and function of the receptor. The members of the calcitonin peptide family bind to the different receptors with varying degrees of activity (see also IAPP gene).

The CGRP receptor consists of a heterodimer with CLR and the receptor activity-modifying protein 1 (RAMP1) (McLatchie et al ). In this heterodimeric protein complex, the ligand binding domain is located between RAMP and CLR (Hay et al 2016). The receptor-mediated increase in intracellular cAMP leads to an activation of protein kinase A, whereupon various factors such as ATP-dependent potassium channels, ERKs (extracellular-signal regulated kinases) and transcription factors such as CREB (cAMP response element-binding protein) are phosphorylated. This enables the transcription of target genes, among other things. The CGRP receptor is mainly expressed in vascular smooth muscle, but also by neurons of the trigeminal ganglion and certain glial cells (Eftekharis et al 2010).

Initial successes have been achieved in rosacea with an anti-CGRP receptor antibody(erenumab) (Wienholtz NKF et al. 2024), a preparation that is primarily used as a migraine drug (Reuter U et al. 2022).

Migraine: CGPR is believed to play a causal role in the development of migraine (Guo et al. 2017). This is underlined by experimental data and clinical study results obtained with monoclonal antibodies that block CGRP or the CGRP receptor highly selectively.

1. Eftekharis S et al. (2013) Differentiation of nerve fibers storing CGRP and CGRP receptors in the peripheral trigeminovascular system. J Pain 14: 1289-1303
2. Guo S et al. (2017) Calcitonin gene-related peptide induced migraine attacks in patients with and without familial aggregation of migraine. Cephalagia 37: 114-124
3. Hay DL et al. (2016) Receptor activity-modifying proteins (RAMPs): New insight and roles. Annu Rev Pharmacol Toxicol 56: 469-487
4. Kukowski B (2018) CGRP signal transduction. Aspects of the development of migraine and current drug therapy approaches. https://www.cme point.de/Fortbildungen/2370_CGRP_CME_FINAL.pdf (retrieved on 1.9.2020)
5. McLatchie LM et al. (1989) RAMPs regulate the transport and ligand specifity of the calcitonin-receptor-like receptor. Nature 393: 333-339
6. Reuter U et al.(2022) Erenumab versus topiramate for the prevention of migraine - a randomized, double-blind, active-controlled phase 4 trial. Cephalalgia 42:108-118.
7. Russel FA et al. (2014) Calcitonin gene-related peptide: physiology and pathophysiology. Physiol Rev 94: 1099-1142
8. Wienholtz NKF et al.(2024) Erenumab for Treatment of Persistent Erythema and Flushing in Rosacea: A Nonrandomized Controlled Trial. JAMA Dermatol 160: 612-619.