Iowa大學的科學家最近的一項新發(fā)現(xiàn)或許能解釋為什么有些人患有偏頭痛，而其他人則沒有,。他們發(fā)現(xiàn)一種微小的蛋白RAMP1會增加神經(jīng)細胞感受器對一種神經(jīng)肽的反應,，從而導致偏頭痛。
這種神經(jīng)肽叫做CGRP,，在發(fā)生偏頭痛時,，血液中的CGRP濃度會上升，而能降低CGRP濃度或者阻礙其作用的藥物能減輕偏頭痛,。如果將CGRP注射入人體內(nèi),，就會導致嚴重的頭痛。這一研究結(jié)果發(fā)表在了3月7日的《Journal of Neuroscience》上,。
UI的分子生理學教授Andrew Russo說：“我們發(fā)現(xiàn)RAMP是管理CGRP的重要蛋白,，所以患有偏頭痛的人其RAMP1濃度也要高于常人。”Russo和同事還發(fā)現(xiàn),，RAMP1在神經(jīng)細胞中的過度表達會增加CGRP受體靈敏度——更多的RAMP1會使CGRP受體對較低的CGRP濃度反應,。
UI小組還在小鼠的神經(jīng)系統(tǒng)中植入人類的RAMP1，結(jié)果這些小鼠的神經(jīng)炎癥是正常小鼠的兩倍,。而神經(jīng)誘導炎癥是偏頭痛的副作用之一,。因此Russo認為，患有偏頭痛的人或許在RAMP1基因上和常人有細微的差別,，這導致了他們體內(nèi)RAMP1濃度的上升,。研究還顯示，植入了RAMP1的小鼠或許是研究偏頭痛以及CGRP工作機制的很好的模型,。
UI小組主要研究了三叉神經(jīng)中的CGRP受體,，三叉神經(jīng)負責頭前部幾乎所有感官知覺的傳輸，包括痛覺和觸覺,。除此之外,，身體里還有其它很多CGRP受體，所以CGRP濃度上升還會導致其它疼痛,，包括關節(jié)炎,。Russo預言，他們小組的發(fā)現(xiàn)將會對除了偏頭痛之外的更多疼痛疾病研究帶來幫助,。
譯自：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: [email protected]
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
