Calcitonin gene-related peptides

Rosenfeld MG, 1983

Calcitonin Gene-Related Peptide (CGRP) is a peptide consisting of 37 amino acids that is formed in the peripheral nervous system and in the central nervous system. Calcitonin Gene-Related Peptide exists in two isoforms, α-CGRP and β-CGRP, which are encoded by 2 different genes located on chromosome 11. While gene CALCA encodes tissue-specific alpha-CGRP and the peptide hormone calcitonin, gene CALB only forms beta-CGRP. Their sequences differ in 3 amino acids.

CGRP belongs to a peptide family that also includes

• amylin
• adrenomedullin
• adrenomedullin 2 and
• calcitonin.

This peptide family consists of functionally and structurally related peptides which, however, have only limited homology. Highly conserved is an amino-terminal ring structure in all of them.

Note: In this paper, a distinction is only made between the two isoforms of CGRP where relevant.

CGRP is one of the most widely used peptides and has multiple biological functions in the human brain, heart, smooth and striated muscles, lungs and gastrointestinal tract (Russel et al. 2014). The CGRP peptide binds to a membrane-bound G-protein coupled receptor. This is a protein complex consisting of a calcitonin-like receptor (CLR) and a single transmembrane protein (RAMP1) (see figure).

Both coding genes (α-calcitonin/CGRP and β-calcitonin/CGRP) consist of 6 exons, from which the calcitonin gene-related peptides are formed by tissue-specific alternative splicing in the nervous system and the calcitonins in the thyroid. The gene loci for α-CGRP and β-CGRP are identical to those for α- and β-Calcitonin, respectively, and are located on chromosome 11.

The expression of Calcitonin (hCT) and CGRP is tissue-specific. While calcitonin is secreted in the parafollicular C cells of the thyroid gland, the CGRP peptide is found almost exclusively in the peripheral and central nervous system. The beta isoform of CGRP is found predominantly in the enteric nervous system. Alpha-CGRP is almost always produced in the peripheral nervous system and here it is mainly found in the nociceptive, sensory neurons of the spinal posterior roots and trigeminal ganglia.

The afferent fibres of these ganglion cells run perivascularly with the arterial and venous blood vessels and are thus present in practically all organs. The large intracerebral vessels also show dense CGRP innervation. After synthesis, CGRP is stored in vesicles and released during neuronal depolarization by calcium-dependent exocytosis - partly with colocalized neuropeptides such as substance P. Perivascularly, this occurs from free nerve endings and axonal varicosities.

For binding to the CGRP receptors CGRP1 and CGRP2, which mediate the physiological effects of the Calcitonin Gene-Related Peptide, the amino acids 8-37 in particular are essential.

Note: Calcitonin Gene-Related Peptide is one of the most potent vasodilators and plays an important role in the pathophysiology of migraine.

CNS and peripheral nervous system: The Calcitonin Gene-Related Peptide is found in high density in the central nervous system, especially in the sensory ganglia, the trigeminal nerve, the cerebral cortex and the pituitary gland (Eftekharis S et al. 2013). The neuropeptide can also be detected at nerve endings of the peripheral nervous system in blood vessels (especially arteries) and in the heart. In the neurons innervating these tissues, the Calcitonin Gene-Related Peptide is colocalized with norepinephrine, vasoactive intestinal peptide (VIP), neuropeptide Y, somatostatin or substance P. In the central nervous system the Calcitonin Gene-Related Peptide is involved in the regulation of body temperature. It is also involved in controlling the release of hormones from the pituitary gland.

Vessels: CGRP itself is a very powerful vasodilator and appears to have a protective effect in several cardiovascular diseases. A CGRP concentration of a few pmol/l already shows clear vasorelaxing effects. This CGRP-induced vasorelaxation is mediated on the one hand by direct smooth muscle relaxation via activation of adenylyl cyclase and on the other hand by an indirect mechanism via release of nitric oxide (NO) from the endothelium.

In hypertension models, CGRP protects against the onset and progression of hypertensive states by potentially inhibiting the pro-hypertensive systems such as the renin-angiotensin-aldosterone system (RAAS) and the sympathetic nervous system.

Heart: CGRP leads directly to positive inotropic and positive chronotropic effects on the heart. CGRP is believed to act as a cardioprotective endogenous mediator released under stress to regulate cardiovascular function.

Kidney: At the kidney, CGRP acts diuretically (increasing glomerular filtration).

Skeleton: At the calcitonin receptor of the osteoclasts, CGRP (unlike calcitonin) has only a weak effect.

Skin and itching: It is known that neuropeptides play a pathogenetic role in skin diseases with itching (Andoh T et al. 2018). Thus, Calcitonin Gene Related Peptide seems to play an important role in psoriatic pruritus, itching in desiccated skin (Andoh T et al. (2018), uremic itching (Du T et al. 2016) or itching in hypertrophic scars (Kwak IS et al. 2014). In experimental approaches it could be demonstrated that multiple "subinflammatory" UV irradiations increase the content of Calcitonin Gene Related Peptide and Substance P (Legat FJ et al 2002). This condition leads to an augmentation of other inflammatory stimuli on skin.

Therapeutic potential: CGRP receptor antagonists are used in the treatment of migraine. CGRP antibodies include

• Eptinezumab
• Erenumab (Aimovig®) does not bind to CGRP but to the CGRP receptor. It is therefore called CGRPR inhibitor. Erenumab is the first antibody for the prophylaxis of migraine in Germany since November 1, 2018 (Aimovig®).
• Fremanezumab (Ajovy®), binds directly to CGRP and neutralizes the peptide.
• Galcanezumab (Emgality®), binds directly to CGRP and neutralizes the peptide.

Due to its vasorelaxing properties, Calcitonin Gene-Related Peptides and CGRP agonists may also be considered as potential drugs in the treatment of coronary heart disease, pulmonary hypertension, erectile dysfunction and peripheral circulatory disorders.

1. Andoh T et al (2018) Non-myelinated C-fibers, but not myelinated A-fibers, elongate into the epidermis in dry skin with itch. Neurosci Lett 672:84-89.
2. Du T et al (2016) Loss of Papillary Dermal Calcitonin Genes Related Peptide-Expressing Neurons Significantly Correlates with Uremic Pruritus. J Invest Dermatol 136:2323-2325.
3. Eftekharis S et al (2013) Differentiation of nerve fibers storing CGRP and CGRP receptors in the peripheral trigeminovascular system. J Pain 14: 1289-1303
4. 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
5. Hay DL et al (2016) Receptor activity-modifying proteins (RAMPs): New insight and roles. Annu Rev Pharmacol Toxicol 56: 469-487
6. 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 (taken on 1.9.2020)
7. Kwak IS et al (2014) Immunohistochemical analysis of neuropeptides (protein gene product 9.5, substance P and calcitonin gene-related peptides) in hypertrophic burn scar with pain and itching. Burns 40:1661-1667.
8. Legat FJ et al (2002) Repeated subinflammatory ultraviolet B irradiation increases substance P and calcitonin gene-related peptide content and augments mustard oil-induced neurogenic inflammation in the skin of rats. Neurosci Lett 329:309-313.
9. McLatchie LM et al (1989) RAMPs regulate the transport and ligand specifity of the Calcitonin-receptor-like receptor. Nature 393: 333-339
10. Rosenfeld MG et al (1983): Production of a novel neuropeptide encoded by the calcitonin gene via tissue specific RNA processing. Nature 304: 129-135.
11. Russel FA et al (2014) Calcitonin gene-related peptides: physiology and pathophysiology. Physiol Rev 94: 1099-1142
12. Tepper SJ et al (2008) Clinical and preclinical rationale for CGRP-receptor antagonists in the treatment of migraine. In: Headache 48: 1259-1268.
13. Tsianakas A et al. (2016) Pruritus in psoriasis: Profile and therapy dermatologist 67:601-605. d
14. Wimalawansa SJ (1996). Calcitonin gene-related peptides and its receptors: molecular genetics, physiology, pathophysiology, and therapeutic potentials. Endocrinol Rev 17: 533-585.