Heteroreceptors Modulating CGRP Release at Neurovascular Junction: Potential Therapeutic Implications on Some Vascular-Related Diseases

Figure 3

CGRPergic neurotransmission at the vascular level. (a) CGRPergic sensory neurons play an important role in the modulation of vascular tone. Indeed, CGRP (from perivascular sensory neurons) can be released from primary afferent fibers. Certainly, CGRP can be also released after activation of TRPV1 channels by capsaicin; if this stimulation is strong enough, an antidromic conduction may be induced and probably also an axonal reflex. Furthermore, a strong stimulus in the periphery could reach the spinal dorsal horn by PAF and consequently could be sent to supraspinal sites. (b) The CGRP release induced by antidromic stimulation, axonal reflex, or activation of TRPV1 channels can be modulated by several heteroreceptors. Most of the heteroreceptors are described as GPCR. Certainly, prejunctional activation of α_2A/2C-adrenoceptors, 5-HT_1B/1F, D₂-like, H_3, and probably Y_1/2 receptors inhibits the CGRPergic neurotransmission in the systemic vasculature. These heteroreceptors are coupled to G _i/o proteins and activation of this system is classically related to inhibition of neurotransmitter release. It is interesting to note that activation of α_2A/2C-adrenoceptors and Y_1/2 receptors supports the role of the sympathetic nerves modulating CGRPergic transmission by noradrenaline and neuropeptide Y (a cotransmitter of sympathetic nerves). (c) At cellular level, the responses to CGRP are mainly mediated by an increase in cAMP by activation of CGRP receptors coupled to G_sα proteins. This atypical receptor belongs to the metabotropic GPCR superfamily and to be functional the CGRP receptor are composed of tree proteins forming a CRLR-RAMP1-RCP complex. At vascular level, the increase in cAMP induces vasorelaxation by a direct (vascular smooth muscle cell) and indirect ( channels) effect. Furthermore, the NOS pathway can be activated. In addition, recruitment of several intracellular signaling involving ERKs or CREBs may be related to the fact that CGRP has protective properties by attenuation of vascular smooth muscle proliferation, hyperplasia inhibition, and stimulation of endothelial cell proliferation. AC, adenylyl cyclase; cAMP, cyclic adenosine monophosphate; CGRP, calcitonin gene-related peptide; CRLR, calcitonin receptor-like receptor; CREB, cAMP response element-binding protein; GPCR, G-protein-coupled receptors; ERKs, extracellular signal-related kinases; , ATP-sensitive potassium channel; NOS, nitric oxide synthase; PAF, primary afferent fibers; PKA, protein kinase A; RAMP1, receptor activity-modifying protein 1; RCP receptor component protein; TRPV1, transient receptor potential vanilloid 1.