Calcitonin Gene-Related Peptides
| Calcitonin-related polypeptide | ||
|---|---|---|
|
||
| CALCA green in the prepeptide, theoretical structure according to PDB 1LS7 | ||
| Mass / length primary structure | 37 amino acids | |
| Precursor | (127/128 aa) | |
| Isoforms | α and β | |
| Identifier | ||
| Gene name (s) | CALCA , CALCB ; CALC1 / CALC2; CGRP-I / II | |
| External IDs | ||
| Occurrence | ||
| Parent taxon | Euteleostomi | |
| Orthologue | ||
| human | House mouse | |
| Entrez | 796 | 12310 |
| Ensemble | ENSG00000110680 | ENSMUSG00000030669 |
| UniProt | P06881 | Q99JA0 |
| Refseq (mRNA) | NM_001002947 | NM_001033954 |
| Refseq (protein) | NP_001029124 | NP_001029126 |
| Gene locus | Chr 11: 14.97 - 14.97 Mb | Chr 7: 114.63 - 114.64 Mb |
| PubMed search | 796 |
12310
|
The calcitonin gene-related peptide ( CGRP ) is a made of 37 amino acids consisting neuropeptide . This peptide is encoded by the same gene as calcitonin and is formed from it in the peripheral and central nervous systems by selective splicing of the mRNA . The calcitonin gene-related peptide is one of the most powerful blood vessel- dilating substances and plays an important role in the pathophysiology of migraines . The calcitonin gene-related peptide was discovered in 1983 by MG Rosenfeld.
biochemistry
Two isoforms of calcitonin gene-related peptides are currently known, α-CGRP and β-CGRP, which differ from one another in three amino acids. The gene loci for α-CGRP and β-CGRP are identical to those for α- and β-calcitonin and are located on chromosome 11 . Both genes (α-calctionin / 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 gland .
Both isoforms of the calcitonin gene-related peptide consist of 37 amino acids. For a binding to the CGRP receptors CGRP 1 and CGRP 2 , which mediate the physiological and pathophysiological effects of the calcitonin gene-related peptide, amino acids 8-37 in particular are essential. In addition, amino acids 1-7 and the presence of a disulfide bond within these amino acids are prerequisites for agonistic activity at the CGRP receptors .
Due to their structural similarity to the calcitonin gene-related peptide, the peptides adrenomedullin and amylin are also assigned to the calcitonin / CGRP family.
Occurrence
The calcitonin gene-related peptide occurs in high density in the central nervous system, especially in the sensory ganglia , the trigeminal nerve , in the cerebral cortex and in the pituitary gland . This neuropeptide can also be detected at nerve endings of the peripheral nervous system in blood vessels (especially arteries ) and in the heart. In these tissues innervating neurons , the calcitonin gene-related peptide comes together with noradrenaline , vasoactive intestinal peptide (VIP), neuropeptide Y , somatostatin and substance P in front.
function
The calcitonin gene-related peptide is one of the strongest blood vessel relaxing substances. Even a CGRP concentration of a few pmol / l shows clear vasorelaxing effects. This CGRP-induced vasorelaxation is mediated on the one hand via direct smooth muscle relaxation via activation of adenylyl cyclase and on the other hand via an indirect mechanism via the release of nitric oxide (NO) from the endothelium . In connection with its properties as an inflammation mediator , a dilatation of the cranial arteries by the calcitonin gene-related peptide is regarded as an essential step in the pathogenesis of migraine.
Furthermore, it leads directly to positive inotropic and positive chronotropic effects on the heart and has mitogenic properties. In the central nervous system, the calcitonin gene-related peptide is involved in the regulation of body temperature. This peptide has a diuretic effect on the kidneys by increasing glomerular filtration . The calcitonin gene-related peptide is also involved in gastric acid secretion and in the control of hormone release from the pituitary gland . On the other hand, it has only weak effects on the calcitonin receptor of the osteoclasts .
Therapeutic potential
The calcitonin gene-related peptides, as well as substances that inhibit its effect ( CGRP receptor antagonists ), are used in the therapy of migraines.
- Erenumab (Aimovig®) does not bind to CGRP, but to the CGRP receptor. It is therefore called a CGRPR inhibitor.
- Fremanezumab (Ajovy®), binds directly to CGRP and neutralizes it.
- Galcanezumab (Emgality®), binds directly to CGRP and neutralizes it.
CGRP receptor agonists
Due to their vasorelaxing properties, the calcitonin gene-related peptides and CGRP agonists and the like. a. discussed as potential drugs in the therapy of coronary artery disease , pulmonary hypertension , erectile dysfunction and peripheral circulatory disorders .
CGRP receptor antagonists
See: Calcitonin Gene Related Peptide Receptor Antagonist
Based on experimental data, CGRP receptor antagonists such as Olcegepant and Telcagepant are currently being developed as potential migraine drugs. In particular, Telcagepant, which was tested in phase III clinical studies , shows an efficacy that is comparable to standard migraine therapeutics, but its clinical development was not continued. Erenumab has been approved as the first antibody for the prophylaxis of migraines in Germany since November 1, 2018 (pre-filled syringe with 70 mg for 4 weeks and, since June 1, 2019, also approved as 140 mg for 4 weeks, trade name Aimovig (R)) and has a significant Additional benefits attested by the Institute for Quality and Efficiency in Health Care (IQWiG) for patients for whom all previously approved prophylactic therapies were unsuccessful. From April 1, 2019, galcanezumab (emgality), which binds CGRP directly, will also be available in Germany. In the United States, erenumab was approved by the FDA in mid-May 2018, followed by fremanezumab (September 14, 2018) and galcanezumab (September 27, 2018).
literature
- Wimalawansa SJ (1996). Calcitonin gene-related peptide and its receptors: molecular genetics, physiology, pathophysiology, and therapeutic potentials. In: Endocrinol. Rev. Vol. 17, pp. 533-585. PMID 8897024
Individual evidence
- ↑ Rosenfeld, MG et al. (1983): Production of a novel neuropeptide encoded by the calcitonin gene via tissue specific RNA processing. In: Nature. Vol. 304, pp. 129-135. PMID 6346105
- ^ Tepper SJ, Stillman MJ: Clinical and preclinical rationale for CGRP-receptor antagonists in the treatment of migraine . In: Headache . 48, No. 8, September 2008, pp. 1259-68. doi : 10.1111 / j.1526-4610.2008.01214.x .
- ↑ Merck Announces Second Quarter 2011 Financial Results