Calcitonin gene-related peptide: physiology and pathophysiology

Abstract

Calcitonin gene-related peptide (CGRP) is a 37-amino acid neuropeptide. Discovered 30 years ago, it is produced as a consequence of alternative RNA processing of the calcitonin gene. CGRP has two major forms (α and β). It belongs to a group of peptides that all act on an unusual receptor family. These receptors consist of calcitonin receptor-like receptor (CLR) linked to an essential receptor activity modifying protein (RAMP) that is necessary for full functionality. CGRP is a highly potent vasodilator and, partly as a consequence, possesses protective mechanisms that are important for physiological and pathological conditions involving the cardiovascular system and wound healing. CGRP is primarily released from sensory nerves and thus is implicated in pain pathways. The proven ability of CGRP antagonists to alleviate migraine has been of most interest in terms of drug development, and knowledge to date concerning this potential therapeutic area is discussed. Other areas covered, where there is less information known on CGRP, include arthritis, skin conditions, diabetes, and obesity. It is concluded that CGRP is an important peptide in mammalian biology, but it is too early at present to know if new medicines for disease treatment will emerge from our knowledge concerning this molecule.

Fig. 1.

A: amino acid residues of human, rat, and mouse α- and β-CGRPs. The secondary structure regions and disulfide bonds are indicated. The residues in bold are nonidentical homologs to the human-α-CGRP. In italics are the residues that are nonidentical homologs between the α- and β-CGRP of the same species. B: processing of the calcitonin CALC I gene leading to either primarily calcitonin in the thyroid or α-CGRP in sensory neurons.

Fig. 2.

CGRP receptor-mediated intracellular signaling. Binding of CGRP ligand to the CLR/RAMP1 receptor can cause activation of multiple signaling pathways and subsequent recruitment of many more downstream effectors. Perhaps the best known is 1) where the activation of adenylate cyclase (AC) by Gα_s provokes the elevation of intracellular cAMP, thereby activating protein kinase A (PKA), resulting in the phosphorylation of multiple downstream targets. These targets may include potassium-sensitive ATP channels (K_ATP channels), extracellular signal-related kinases (ERKs), or transcription factors, such as cAMP response element-binding protein (CREB). Nitric oxide generation following CGRP receptor activation may be secondary to phosphorylation of nitric oxide synthase (NOS), although this has not been directly shown. Alternatively, the CGRP receptor may couple to Gα_i/o, thus attenuating AC activity and decreasing intracellular cAMP, resulting in a loss of PKA activity (2). Reports in osteoblasts have also shown evidence of Gα_q/11-mediated signaling (3), involving activation of PLC-β1, cleaving phosphatidylinositol 4,5-bisphosphate (PIP₂) to form inositol trisphosphate (IP₃) and diacylglycerol (DAG). IP₃ binds to the IP₃ receptor (IP₃R) on the endoplasmic reticulum (ER), causing calcium release and thus raising cytoplasmic concentrations. DAG may activate PKC-ϵ, which in turn phosphorylates proteins further downstream. Finally, there is evidence to suggest G protein-independent signaling pathways (4) that require the translocation of scaffolding proteins such as β-arrestins (β-Arr) to the activated receptor. Additionally, βγ G protein subunits may signal in a unique way to specifically terminate endothelin (ET)-mediated effects. Solid arrows represent known pathways, and broken arrows represent potential new pathways. CGRP, calcitonin gene-related peptide; CLR, calcitonin receptor-like receptor; RAMP1, receptor activity-modifying protein 1; RCP, receptor component protein.

Fig. 3.

A diagram representing the interactions between the sensory nerves, skin, and arterioles. Antidromic sensory nerve stimulation results in an electrical impulse firing towards the spinal cord and axon reflex to the peripheral vasculature, where CGRP is released from the nerve terminals acting on the arterioles, causing vasodilatation. CGRP can mediate this response by: 1) directly activating its receptors on the vascular smooth muscles and mediating relaxation via the Gα_s pathway; and 2) activating receptors on endothelial cells to enhance NO production, which can diffuse into the vascular smooth muscles to mediate vasorelaxation via GC activation. CGRP is also released from the central projections of DRG neurons where it may play a role in central sensitization. AC, adenylyl cyclase; eNOS, endothelial nitric oxide synthase; GC, guanylyl cyclase; NO, nitric oxide; PKA, protein kinase A; PKG, protein kinase G; VSMC, vascular smooth muscle cell.

Fig. 4.

Local and systemic mechanisms involving CGRP in cardiovascular regulation. Locally (e.g., in skin), CGRP is released from the peripheral sensory nerve endings (left). CGRP acts to increase blood flow, in a long-acting manner, which can lead to involvement in neurogenic inflammation and as a regulatory factor in inflammation. These effects can contribute to enhanced wound healing. Systemically, CGRP is not considered to have a major role in the normal individual. However, animal studies imply that CGRP may delay or protect against cardiovascular disease (right). This leads to protection against hypertension, hypertrophy, and inflammation and may be via direct mechanisms, or indirectly as a consequence of vasodilator activity.

Fig. 5.

CGRP is involved in the pathophysiology of migraine. CGRP is released from trigeminal afferent nerve fibers during a migraine and causes vasodilatation and neurogenic inflammation. Raised levels of CGRP are observed both peripherally and centrally in migraine patients. CGRP antibodies and antagonists are thought to reduce migraine by reducing these CGRP levels or through blocking the actions of CGRP. CGRP antibodies are peripherally restricted, whereas CGRP antagonists may have central actions.

Fig. 6.

Summary of disease conditions where CGRP plays a role. CGRP can be targeted pharmacologically with either the use of a CGRP analog to increase CGRP levels or a CGRP antagonist to block the actions of CGRP. These approaches are shown against the conditions that may benefit. For some conditions, e.g., diabetes, it is not yet clear whether CGRP supplementation or CGRP inhibition would be the most beneficial approach.