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The Journal of Neuroscience, March 7, 2007, 27(10):2693-2703; doi:10.1523/JNEUROSCI.4542-06.2007

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Cellular/Molecular
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. Russo^1,2

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{at}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

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Received Oct. 19, 2006; revised Jan. 24, 2007; accepted Jan. 24, 2007.

Correspondence should be addressed to Andrew F. Russo, Department of Molecular Physiology and Biophysics, University of Iowa, Iowa City, IA 52242. Email: andrew-russo{at}uiowa.edu

This article has been cited by other articles:

				M. Simonetti, R. Giniatullin, and E. Fabbretti Mechanisms Mediating the Enhanced Gene Transcription of P2X3 Receptor by Calcitonin Gene-related Peptide in Trigeminal Sensory Neurons J. Biol. Chem., July 4, 2008; 283(27): 18743 - 18752. [Abstract] [Full Text] [PDF]

				P. J. Goadsby Calcitonin gene-related peptide (CGRP) antagonists and migraine: Is this a new era? Neurology, April 15, 2008; 70(16): 1300 - 1301. [Full Text] [PDF]

				K.-Y. Park and A. F. Russo Control of the Calcitonin Gene-related Peptide Enhancer by Upstream Stimulatory Factor in Trigeminal Ganglion Neurons J. Biol. Chem., February 29, 2008; 283(9): 5441 - 5451. [Abstract] [Full Text] [PDF]

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