Role of calcitonin gene-related peptide in cerebral vasospasm, and as a therapeutic approach to subarachnoid hemorrhage

Abstract

Calcitonin gene-related peptide (CGRP) is one of the most potent microvascular vasodilators identified to date. Vascular relaxation and vasodilation is mediated via activation of the CGRP receptor. This atypical receptor is made up of a G protein-coupled receptor called calcitonin receptor-like receptor (CLR), a single transmembrane protein called receptor activity-modifying protein (RAMP), and an additional protein that is required for Ga(s) coupling, known as receptor component protein (RCP). Several mechanisms involved in CGRP-mediated relaxation have been identified. These include nitric oxide (NO)-dependent endothelium-dependent mechanisms or cAMP-mediated endothelium-independent pathways; the latter being more common. Subarachnoid hemorrhage (SAH) is associated with cerebral vasoconstriction that occurs several days after the hemorrhage and is often fatal. The vasospasm occurs in 30-40% of patients and is the major cause of death from this condition. The vasoconstriction is associated with a decrease in CGRP levels in nerves and an increase in CGRP levels in draining blood, suggesting that CGRP is released from nerves to oppose the vasoconstriction. This evidence has led to the concept that exogenous CGRP may be beneficial in a condition that has proven hard to treat. The present article reviews: (a) the pathophysiology of delayed ischemic neurologic deficit after SAH (b) the basics of the CGRP receptor structure, signal transduction, and vasodilatation mechanisms and (c) the studies that have been conducted so far using CGRP in both animals and humans with SAH.

Keywords: CGRP; G proteins; GPCR; cerebral vasospasm; subarachnoid hemorrhage.

FIGURE 1

Tissue-specific expression of the calcitonin gene by alternative splicing.Splicing of alternative exons leads to two different mRNAs. The mRNA encoding calcitonin is found predominantly in the thyroid C cell; the mRNA encoding a CGRP is found predominantly in the hypothalamus and other nervous tissue. CGRP, calcitonin gene related peptide; mRNA, messenger RNA; CCP, calcitonin carboxyl-terminal peptide. FromAmara et al. (1982), with permission.

FIGURE 2

Structure of CGRP receptor. CGRP receptor components and important residues for receptor signaling and internalization. The CGRP receptor is formed by CLR (blue), RAMP1 (yellow), and RCP (orange). Functionally important residues are shown as single letter abbreviations. CGRP, calcitonin gene-related peptide; CLR, calcitonin receptor-like receptor; RAMP, receptor activity-modifying protein; RCP, receptor component protein; C′, C-terminal; EC, extracellular loop; ICL, intracellular loop; N′, N-terminal; TM, transmembrane. FromWalker et al. (2010), with permission.

FIGURE 3

CGRP receptor-mediated intracellular signaling. (A) Ga_s signaling increases AC (green) activity, elevating intracellular cAMP, activating PKA and subsequently many potential downstream effectors. (B) The CGRP receptor might also couple to Ga_i/o, reducing AC (red) activity, decreasing intracellular cAMP and reducing PKA activity. (C) CGRP signaling via Ga_q activates PLC-b, which cleaves PIP₂ into IP₃ and DAG, resulting in elevated intracellular Ca²⁺ and PKC activation. (D) The CGRP receptor might also utilize Ga-independent signaling, and G_βγ- or b-arrestin-mediated signaling pathways. Arrows represent reported pathways; broken arrows represent potential or inferred pathways. CGRP, calcitonin gene-related peptide; CLR, calcitonin receptor-like receptor; Gα, α subunit of the G protein; NO, nitric oxide; NOS, nitric oxide synthase; AC, adenylyl cyclase; cAMP, cyclic adenosine monophosphate; PKA, protein kinase A; PKC, protein kinase C; RCP, receptor component protein; AC, adenylate cyclase; ER, endoplasmic reticulum; PIP₂, phosphatidylinositol 4,5-bisphosphate; DAG, diacylglycerol. FromWalker et al. (2010), with permission.