Iowa大学的科学家最近的一项新发现或许能解释为什么有些人患有偏头痛，而其他人则没有。他们发现一种微小的蛋白RAMP1会增加神经细胞感受器对一种神经肽的反应，从而导致偏头痛。
这种神经肽叫做CGRP，在发生偏头痛时，血液中的CGRP浓度会上升，而能降低CGRP浓度或者阻碍其作用的药物能减轻偏头痛。如果将CGRP注射入人体内，就会导致严重的头痛。这一研究结果发表在了3月7日的《Journal of Neuroscience》上。
UI的分子生理学教授Andrew Russo说：“我们发现RAMP是管理CGRP的重要蛋白，所以患有偏头痛的人其RAMP1浓度也要高于常人。”Russo和同事还发现，RAMP1在神经细胞中的过度表达会增加CGRP受体灵敏度——更多的RAMP1会使CGRP受体对较低的CGRP浓度反应。
UI小组还在小鼠的神经系统中植入人类的RAMP1，结果这些小鼠的神经炎症是正常小鼠的两倍。而神经诱导炎症是偏头痛的副作用之一。因此Russo认为，患有偏头痛的人或许在RAMP1基因上和常人有细微的差别，这导致了他们体内RAMP1浓度的上升。研究还显示，植入了RAMP1的小鼠或许是研究偏头痛以及CGRP工作机制的很好的模型。
UI小组主要研究了三叉神经中的CGRP受体，三叉神经负责头前部几乎所有感官知觉的传输，包括痛觉和触觉。除此之外，身体里还有其它很多CGRP受体，所以CGRP浓度上升还会导致其它疼痛，包括关节炎。Russo预言，他们小组的发现将会对除了偏头痛之外的更多疼痛疾病研究带来帮助。
译自：physorg.com
部分英文原文:
The Journal of Neuroscience, March 7, 2007, 27(10):2693-2703; doi:10.1523/JNEUROSCI.4542-06.2007
Sensitization of Calcitonin Gene-Related Peptide Receptors by Receptor Activity-Modifying Protein-1 in the Trigeminal Ganglion
Zhongming Zhang,1 Christina S. Winborn,2 Blanca Marquez de Prado,1 and Andrew F. Russo1,2
1Department of Molecular Physiology and Biophysics, and 2Genetics Program, University of Iowa, Iowa City, Iowa 52242
Correspondence should be addressed to Andrew F. Russo, Department of Molecular Physiology and Biophysics, University of Iowa, Iowa City, IA 52242. Email: andrew-russo@uiowa.edu
The neuropeptide calcitonin gene-related peptide (CGRP) from the trigeminal ganglion has been established as a key player in the pathogenesis of migraine. In this study, we provide evidence that the responsiveness of neuronal CGRP receptors is strongly enhanced in vitro and in vivo by expression of human receptor activity-modifying protein-1 (hRAMP1), an obligatory subunit of the CGRP receptor. We first demonstrated that activation of CGRP receptors on cultured trigeminal ganglion neurons increased endogenous CGRP mRNA levels and promoter activity. The promoter activation was cAMP dependent and blocked by the antagonist BIBN4096BS [1-piperidinecarboxamide, N-[2-[[5-amino-L-[[4-(4-pyridinyl)-l-piperazinyl]carbonyl]pentyl]amino]-1-[(3,5-dibromo-4-hydroxyphenyl)methyl]-2-oxoethyl]-4-(1,4-dihydro-2-oxo-3(2H)-quinazolinyl)], a new antimigraine drug. Gene transfer using an adenoviral hRAMP1 expression vector increased the maximal production of cAMP by 1.8 ± 0.2-fold and decreased the EC50 to 2.3 ± 0.8 nM from 9.0 ± 5.9 nM and 15.6 ± 5.2 nM in uninfected and control-infected cultures, respectively. To establish whether RAMP1 is limiting in vivo as indicated from the culture studies, a transgenic mouse expressing hRAMP1 in the nervous system was generated. After CGRP injection into the whiskerpad, the hRAMP1 transgenic mice displayed 2.2 ± 0.2-fold greater plasma extravasation, which is a measure of neurogenic inflammation. These results demonstrate that RAMP1 is functionally rate limiting for CGRP receptor activity in the trigeminal ganglion, which raises the possibility that elevated RAMP1 might sensitize some individuals to CGRP actions in migraine.
Key words: migraine; CGRP; neurogenic inflammation; calcitonin; Cre-transgenic; cAMP; gene transfer; GPCR; transcription; transgenic; trigeminal
