Distribution of CGRP

CGRP expression is widely distributed in the central and peripheral nervous system. In the brain, it is particularly concentrated in the hypothalamus and in certain nuclei of the brainstem. In the periphery, CGRP is mainly detected in sensory afferents projecting to the spinal cord, in motor neurons at the neuromuscular junctions and in nerve fibers associated with the vasculature. In capsaicin-sensitive sensory neurons, CGRP co-localizes with substance P and other neuropeptides, in the motor endplate with acetylcholine.

Physiological Functions

On the basis of pharmacological studies several physiological functions of CGRP have been suggested. Due to its potent vasodilatory action and its inotropic and chronotropic effects, CGRP is likely to play a role in cardiovascular homeostasis. Furthermore, it influences feeding and digestion since it has been shown to decrease food intake, gastric secretion, and intestinal motility. Based on its ability to modulate substance P signaling, an additional function of CGRP in nociception has been proposed. Additionally, CGRP might be important in processes such as control of fetoplacental vascular tone, regulation of calcium metabolism and insulin secretion, acetylcholine receptor synthesis, peripheral nerve regeneration, and neurogenic inflammation.

CGRP Receptors

CGRP receptors have been identified in several tissues, including brain, cardiovascular, endothelial, and smooth muscle tissue.

Based on early pharmacological studies, the existence of two classes, CGRP1 and CGRP2 receptors, has been described. According to this historical classification CGRP1 receptors are more sensitive to the antagonistic properties of α-CGRP (8-37) (4013696, 4034544) whereas CGRP2 receptors are more responsive to the agonistic CGRP analogs, (Cys(Acm)^2,7-α-CGRP (human) (4039880) and (Cys(Et)^2,7)-α-CGRP (human) (4039888). Recent studies have shown that the previously cloned G protein-coupled orphan receptor, named calcitonin receptor-like receptor (CRLR), can interact with members of a new family of three single-transmembrane domain receptor activity-modifying proteins (RAMPs). Interaction with RAMP1 resulted in a CGRP receptor, which is sensitive to α-CGRP (8-37), whereas binding to RAMP2 and RAMP3 led to receptors for adrenomedullin known as AM1 and AM2 receptors, respectively. The AM2 receptor showed considerable affinity for CGRP. Besides their essential role in regulating ligand specificity.

RAMPs are also required for membrane trafficking of CRLR. Recently, a receptor component protein (RCP) of the CRLR/RAMP1 complex was described. RCP is an intracellular protein which is highly conserved between species and might be required for G protein-coupled signal transduction.

Therapeutic Implications

Given the multitude of physiological and pathophysiological effects of CGRP, modulations of its properties represent potential therapeutic interventions in a variety of disease states including cardiovascular disorders and neurogenic inflammation.

Clinical trials have indicated that the vasodilatory effect of CGRP might be beneficial in the treatment or prevention of Raynaud’s disease, hypertension, angina pectoris and heart failure. Since CGRP is rapidly metabolized, longer acting CGRP agonists are needed for long-term treatment. CGRP antagonists, for their part, have found use in the treatment of migraine, which involves the activation of the trigeminal system and CGRP-evoked dilatation of cranial vessels.

CGRP as Cardioprotectant

CGRP is also present in the heart. Infusion of the peptide induces vasodilation and generates positive inotropic and chronotropic effects, which can be blocked by its antagonist, truncated CGRP 8-37. In case of myocardial ischemia, CGRP is released by cardiac adrenergic cells. In response, an increase of plasma CGRP can be detected. The peptide is involved in protecting the heart against ischemia-reperfusion injury. Unfortunately, the short half-life of CGRP limits its therapeutic use in the treatment of cardiovascular disorders. So long-acting CGRP agonists have gained interest. They also show potential in the management of hypertension. Stabilization of peptidic agonists could be achieved by conjugation of long-chain fatty acids. N-terminally lipidated α-CGRP analogs have been developed and tested in murine models of hypertension and heart failure. Long-time administration of such an analog in vivo eventually resulted in a reduction in food intake and body weight. The modified peptide hormone induced secretion of GLP-1.

As an alternative approach for tackling the low metabolic stability of the peptide, controlled-release formulations of α-CGRP for treatment of ischemia due to a myocardial infarction have been developed.

CGRP and Migraine

CGRP has been detected in pericranial vascular nerves and the trigeminal ganglion. The neuropeptide is a potent dilator of cerebral and dural vessels, and it is involved in meningeal dural vasodilation. Migraine is possibly caused by activation of the human trigeminal system and the release of CGRP. Increased cranial CGRP levels have been measured in patients suffering from episodic or chronic migraine. Infusion of the peptide can trigger migraine attacks. Hence, CGRP antagonists could be effective in the treatment of the disease, which afflicts about 15 to 18% of the population worldwide. The recurrent pulsating strong headache and other symptoms turn migraine into a leading cause of disability and a global health problem. Women carry a higher risk of developing the disease than men.

References

Product Monograph Calcitonin Gene-Related Peptides

Calcitonin gene-related peptide (CGRP) plays a key role in the pathophysiology of migraine, a common disabling brain disorder. The release of CGRP causes inflammation in the meninges, the membranous coverings of the brain, and is the cause of migraine pain for most patients. There is a need for new treatments in the migraine market because acute treatments have relied on triptan drugs. Some patients are unresponsive to triptans and others cannot use triptans because they have or are at a risk of cardiovascular problems (1). In 2018, the first anti-CGRP receptor monoclonal antibody, Aimovig^® (erenumab), was approved in the United States. There are several promising candidates in clinical development that target CGRP and the CGRP receptor as shown in Table 1.