Calcitonin gene‐related powerpeptide and its puzzling receptor

Calcitonin gene-related peptide (CGRP) exists in two homologous isoforms. The aand b-isoforms of CGRP differ by only one to three amino acid residues in different species and consequently have similar activities. Yet, while the b-isoform, also called CGRP II, has its ‘own’ gene, the a peptide (or CGRP I, hereafter referred to simply as CGRP) is a product of alternative RNA splicing of the calcitonin (CT) gene (Amara et al. 1982). Calcitonin gene-related peptide really is a misnomer of this multi-faceted and powerful peptide. Indeed, while the parental gene encodes for both calcitonin (CT) and CGRP, the peptide hormone calcitonin is almost exclusively expressed in the parafollicular cells of the thyroid gland. Moreover, the role of CT in calcium homeostasis is sometimes questioned, at least in adult humans. On the other hand, the alternative splice product of the CT gene has since its discovery in 1982 proven to be a powerful multi-functional peptide. At least part of this diversity seems to be related to the wide distribution and the unusual character of the CGRP receptor. In the current issue of Acta Physiologica, Edvinsson et al. (2014) localized and characterized this receptor in human subcutaneous arteries and made further interesting observations. Calcitonin gene-related peptide is expressed in a discrete set of neurones of the central and peripheral nervous system. However, most organ systems are innervated by peripheral CGRP containing nerves, and CGRP receptors have been reported in many tissues including brain, liver, kidney, and cardiac, skeletal and uterine and vascular smooth muscle (Poyner 1992). CGRP is one of the most powerful of the vasodilator transmitters found (Brain et al. 1985). Yet, the effects of this multi-faceted peptide are not confined to blood vessels. In the cochlea, for example, the peptide is released from efferent fibres mainly innervating the primary afferents contacting the inner hair cells, thereby boosting the sound-evoked firing of the afferents and, hence, their dynamic range (Russo & Dickerson 2006). In skeletal muscle, CGRP is released from sensory nerve terminals as well as from the motor terminals at the neuromuscular junction. While CGRP released at the end plate modulates the expression of the nicotinic acetylcholine receptor (nAChR), and of acetylcholine esterase, the enzyme degrading acetylcholine, it potentiates the effect of acetylcholine by increasing the open probability of the nAChR (Lu et al. 1993). Released from sensory nerves in the muscle (Sakaguchi et al. 1991), the substance not only dilates the microvessels in the muscle (Loaiza et al. 2002), it also influences the excitability of the skeletal muscle fibres by increasing their Na/K pump activity, altering their Na channel function (MacDonald et al. 2008) and stimulating their voltage-gated Ca release by increasing the s.r. Ca content and influencing the density of dihydropyridine receptors in the T tubular membrane (Vega & Avila 2010). The mechanism involved in vasorelaxation to CGRP seems also to vary among species and vessel types. In some vessels such as the rat aorta and pulmonary artery, CGRP interacts with endothelial receptors stimulating the release of endothelium-derived relaxing factors, as both endothelium removal and blocking NO synthesis significantly reduces CGRPinduced vasorelaxation. In cat cerebral, pig coronary and rat mesenteric vessels, however, CGRP acts directly on the smooth muscle cells. A number of studies have shown that CGRP relaxes tension by increasing the cyclic AMP content in vascular smooth muscle (e.g. Kageyama et al. 1993). The resultant activation of protein kinase A (PKA) has been shown to open ATP-dependent K (KATP) channels (Nelson et al. 1990), hyperpolarizing and relaxing the tissue. However, in a number of vascular preparations, PKAdependent vasodilators have been shown to activate smooth muscle BKCa channels. Indeed, other studies on isolated rat and porcine coronary arteries have not been able to demonstrate a possible involvement of ATP-sensitive K channel opening in CGRP-induced vasorelaxation (Prieto et al. 1991, Kageyama et al. 1993). In rat gastric arteries, we have found the vasorelaxation to CGRP to be partly sensitive to TEA, suggesting the involvement of BKCa channel activation (Breyne et al. 2006). More recently, we directly showed an increase in BKCa channel current in freshly isolated smooth muscle cells from rat mesenteric arteries, an effect which was PKA dependent (Bol et al. 2012). Even in the same vessel, the mechanism of smooth muscle relaxation can vary depending on precontraction level. In preconstricted rat coronary arteries, CGRP-induced vasorelaxation was mediated by BKCa, while in resting arteries, KATP was shown to be additionally involved in the CGRP-induced decrease in [Ca]i and basal tension (Sheykhzade & Nyborg 2001). Besides lowering intracellular calcium levels