Journal article
Sensitization of Calcitonin Gene-Related Peptide Receptors by Receptor Activity-Modifying Protein-1 in the Trigeminal Ganglion
The Journal of neuroscience, Vol.27(10), pp.2693-2703
03/07/2007
DOI: 10.1523/JNEUROSCI.4542-06.2007
PMCID: PMC6672495
PMID: 17344407
Abstract
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(2
H
)-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 EC
50
to 2.3 ± 0.8 n
m
from 9.0 ± 5.9 n
m
and 15.6 ± 5.2 n
m
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.
Details
- Title: Subtitle
- Sensitization of Calcitonin Gene-Related Peptide Receptors by Receptor Activity-Modifying Protein-1 in the Trigeminal Ganglion
- Creators
- Zhongming Zhang - Department of Molecular Physiology and Biophysics, andChristina S Winborn - Genetics Program, University of Iowa, Iowa City, Iowa 52242Blanca Marquez de Prado - Department of Molecular Physiology and Biophysics, andAndrew F Russo - Department of Molecular Physiology and Biophysics, and
- Resource Type
- Journal article
- Publication Details
- The Journal of neuroscience, Vol.27(10), pp.2693-2703
- DOI
- 10.1523/JNEUROSCI.4542-06.2007
- PMID
- 17344407
- PMCID
- PMC6672495
- NLM abbreviation
- J Neurosci
- ISSN
- 0270-6474
- eISSN
- 1529-2401
- Publisher
- Society for Neuroscience
- Language
- English
- Date published
- 03/07/2007
- Academic Unit
- Neurology; Molecular Physiology and Biophysics; Pathology; Iowa Neuroscience Institute; Craniofacial Anomalies Research Center
- Record Identifier
- 9984014019902771
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