CGRP Receptor

The neuropeptide calcitonin gene-related peptide (CGRP) is proposed to play a central role in the underlying pathology of migraine. CGRP and its receptor are widely expressed in both the peripheral and central nervous systems by multiple cell types involved in the regulation of inflammatory and nociceptive responses. Peripheral release of CGRP from trigeminal nerve fibres within the dura and from the cell body of trigeminal ganglion neurons is likely to contribute to peripheral sensitization of trigeminal nociceptors. Similarly, the release of CGRP within the trigeminal nucleus caudalis can facilitate activation of nociceptive second-order neurons and glial cells. Thus, CGRP is involved in the development and maintenance of persistent pain, central sensitization and allodynia, events characteristic of migraine pathology.

1050381-35-5
BMS694153
1050381-35-5
CGRP 8-37 (human)
119911-68-1
Amylin
122384-88-7
Amylin (rat)
124447-81-0
1289023-67-1
Rimegepant
1289023-67-1
CGRP 8-37 (rat)
129121-73-9
1374248-77-7
Ubrogepant
1374248-77-7
B0084-441440
Olcegepant
204697-65-4
SB 268262
217438-17-0
586368-06-1
781649-09-0
Telcagepant
781649-09-0
α-CGRP (rat)
83651-90-5
α-CGRP (human)
90954-53-3
957116-20-0
MK-3207 HCl
957116-20-0
957118-49-9
MK-3207
957118-49-9

Background


Calcitonin gene related peptide (CGRP) is a 37 amino acid sensory-nerve derived neuropeptide. It is widely distributed in sensory nerves throughout the central and peripheral nervous system (spleen, around blood vessels, in primary and secondary lymphoid tissue). CGRP was discovered when alternative processing of RNA transcripts from the calcitonin gene was shown to result in the production of distinct mRNAs encoding CGRP. CGRP is a member of the Calcitonin/CGRP family of bioactive peptides that comprises calcitonin, amylin, two CGRP’s (α and β) and adrenomedullin (ADM). It has a range of biological activities but it is best known for its vasodilator activity, especially at the microvascular level.

CGRP has multiple effects in the lymphoid system and at inflammation sites where it is released along with another sensory neuropeptide, substance P. Substance P and CGRP are central neuromediators in nociception and neurogenic inflammation. These neuropeptides are located in a subset of small dorsal root ganglion neurons, which give rise to the lightly myelinated A delta and unmyelinated C fibers. Stimulation of C fibers releases SP and CGRP peripherally and in the dorsal spinal cord. Substance P and CGRP produce symptoms of neurogenic inflammation by interacting with endothelial cells, mast cells, immune cells, and arterioles. It was also found to have a central role in the pathophysiology of migraines.

Primary headaches and migraines are among the most prevalent neurological disorders, afflicting up to 16% of the adult population. The associated pain originates from intracranial blood vessels that are innervated by sensory nerves storing several neurotransmitters. In primary headaches and migraines, there is a clear association between the headache and the release of CGRP, but not other neuronal messengers. Acute treatment with administration of a 5-HT (1B/1D) agonist (triptan) results in alleviation of the headache and normalization of the CGRP level. The mechanism of action of triptans involves vasoconstriction of intracranial vessels and a presynaptic inhibitory effect of sensory nerves. The central role of CGRP in migraine and cluster headache pathophysiology has led to the search for small-molecule CGRP antagonists, which are predicted to have fewer cardiovascular side effects in comparison to the triptans. CGRP antagonists CGRP8-37 and BIBN 4096 BS are the main target of numerous clinical studies, some with very encouraging results for migraine patients.

CGRP’s biological effects are due to its high affinity binding to specific CGRP receptors. CGRP receptors are found throughout the body including the nervous, endocrine, cardiovascular systems and spleen. The CGRP receptor is a G protein coupled receptor made up of 3 major components: calcitonin receptor like receptor (CRLR), receptor associated modulating protein (RAMP 1) and the adaptor protein receptor component protein (RCP) that couples the CGRP binding with downstream signal transduction. It has the structure of a typical GPCR with seven transmembrane helices and is encoded by the Calcitonin Receptor Like Receptor (CRLR). The CRLR receptor is associated with accessory proteins called receptor activity modifying proteins (RAMP's) that determine its ligand specificity. These proteins are responsible for the proper glycosylation, transport to the cell surface, internalization and degradation of the receptor. CRLR and RAMP 1 form a specific receptor for CGRP, CRLR and RAMP 2 are specific for Adrenomedulin (ADM). The association between CRLR and RAMP 3 was recently described as a low affinity receptor for both CGRP and ADM with regulatory roles in the overall receptor turnover. Another CGRP receptor component called CGRP Receptor Component Protein (RCP) was described. RCP is a low molecular weight intracellular membraneassociated protein that couples the CGRP receptor to the cellular signal transduction pathway. Its functions are not well established yet but recent studies demonstrated its participation in downstream signaling processes and receptor recycling.

Reference:

Ciornei, Radu-Tudor. A Protective Effect of Calcitonin Gene Related Peptide (CGRP) on Developing B Cells. ProQuest, 2007.