IMMUNOHISTOCHEMICAL LOCALIZATION OF THE CALCITONIN GENE-RELATED PEPTIDE BINDING SITE IN THE PRIMATE TRIGEMINOVASCULAR SYSTEM USING FUNCTIONAL ANTAGONIST ANTIBODIES
IMMUNOHISTOCHEMICAL LOCALIZATION OF THE CALCITONIN GENE-RELATED PEPTIDE BINDING SITE IN THE PRIMATE TRIGEMINOVASCULAR SYSTEM USING FUNCTIONAL ANTAGONIST ANTIBODIES
复制标题
DOI：
10.1016/j.neuroscience.2016.04.046
复制
发表时间：
2016-07-22
期刊：
影响因子：
3.3
通讯作者：
Edvinsson, Lars
中科院分区：
文献类型：
--
作者：
Miller, Silke;Liu, Hantao;Edvinsson, Lars
Calcitonin gene-related peptide (CGRP) is a potent vasodilator and a neuromodulator implicated in the pathophysiology of migraine. It binds to the extracellular domains of calcitonin receptor-like receptor (CLR) and receptor activity-modifying protein (RAMP) 1 that together form the CGRP receptor. Antagonist antibodies against CGRP and its binding site at the receptor are clinically effective in preventing migraine attacks. The blood-brain barrier penetration of these antagonist antibodies is limited, suggesting that a potential peripheral site of action is sufficient to prevent migraine attacks. To further understand the sites of CGRP-mediated signaling in migraine, we used immunohistochemical staining with recently developed antagonist antibodies specifically recognizing a fusion protein of the extracellular domains of RAMP1 and CLR that comprise the CGRP binding pocket at the CGRP receptor in monkey and man. We confirmed binding of the antagonist antibodies to human vascular smooth muscle cells (VSMCs) of dural meningeal arteries and neurons in the trigeminal ganglion, both of which are likely sites of action for therapeutic antibodies in migraine patients. We further used one of these antibodies for detailed mapping on cynomolgus monkey tissue and found antagonist antibody binding sites at multiple levels in the trigeminovascular system: in the dura mater VSMCs, in neurons and satellite glial cells in the trigeminal ganglion, and in neurons in the spinal trigeminal nucleus caudalis. These data reinforce and clarify our understanding of CGRP receptor localization in a pattern consistent with a role for CGRP receptors in trigeminal sensitization and migraine pathology. (C) 2016 IBRO. Published by Elsevier Ltd. All rights reserved.
