Journal article
CGRP receptor activity in mice with global expression of human receptor activity modifying protein 1
British journal of pharmacology, Vol.174(12), pp.1826-1840
06/2017
DOI: 10.1111/bph.13783
PMCID: PMC5446571
PMID: 28317098
Abstract
CGRP is a potent vasodilator and nociceptive neuropeptide linked to migraine. CGRP receptors are heterodimers of receptor activity modifying protein 1 (RAMP1) and either calcitonin receptor-like receptor (CLR; forms canonical CGRP receptor) or calcitonin receptor (CT receptor; forms AMY
receptor). The goal of this study was to test whether transgenic mice globally expressing human RAMP1 have increased CGRP receptor activity and whether the receptors are sensitive to human selective antagonist telcagepant.
cAMP production was measured in primary cultures of aortic smooth muscle and trigeminal ganglia neurons from global hRAMP1 mice and non-transgenic littermates. Functional activity and inhibition were compared with clonal cell lines expressing combinations of CLR or CT receptors with RAMP1.
Cultured smooth muscle from global hRAMP1 mice had a 10-fold greater CGRP-induced cAMP maximal response (Rmax) than non-transgenic littermates, with similar EC
s. In contrast, cultured trigeminal ganglia from global hRAMP1 mice had a 40-fold leftward shift of the EC
, with similar Rmax values as littermates. In both hRAMP1 cultures, telcagepant blocked CGRP-induced cAMP production, but was not effective in non-transgenic cultures. IC
values were closer to those observed for CT receptor/hRAMP1 than CLR/hRAMP1 in clonal cell lines.
Overexpression of hRAMP1 increases CGRP signalling by changing the maximal response or ligand sensitivity, depending on tissue type. Furthermore, telcagepant inhibited transgenic hRAMP1 CGRP receptors, but the degree of inhibition suggests that the transgenic mice are only partially humanized or both canonical CGRP and AMY
receptors are functional in trigeminal ganglia neurons and vascular smooth muscle.
Details
- Title: Subtitle
- CGRP receptor activity in mice with global expression of human receptor activity modifying protein 1
- Creators
- Keegan J Bohn - Department of Molecular Physiology and Biophysics, University of Iowa, Iowa City, IA, USABaolin Li - Neuroscience Research Division, Eli Lilly and Company, Lilly Corporate Center, Indianapolis, IN, USAXiaofang Huang - Neuroscience Research Division, Eli Lilly and Company, Lilly Corporate Center, Indianapolis, IN, USABianca N Mason - Molecular and Cellular Biology Program, University of Iowa, Iowa City, IA, USAAnne-Sophie Wattiez - Department of Molecular Physiology and Biophysics, University of Iowa, Iowa City, IA, USAAdisa Kuburas - Department of Molecular Physiology and Biophysics, University of Iowa, Iowa City, IA, USAChristopher S Walker - Maurice Wilkins Centre and Centre for Brain Research, School of Biological Sciences, University of Auckland, Auckland, New ZealandPeiyi Yang - Quantitative Biology, Eli Lilly and Company, Lilly Corporate Center, Indianapolis, IN, USAJianliang Yu - Quantitative Biology, Eli Lilly and Company, Lilly Corporate Center, Indianapolis, IN, USABeverly A Heinz - Quantitative Biology, Eli Lilly and Company, Lilly Corporate Center, Indianapolis, IN, USAKirk W Johnson - Neuroscience Research Division, Eli Lilly and Company, Lilly Corporate Center, Indianapolis, IN, USAAndrew F Russo - Veterans Affairs Medical Center, Iowa City, IA, USA
- Resource Type
- Journal article
- Publication Details
- British journal of pharmacology, Vol.174(12), pp.1826-1840
- DOI
- 10.1111/bph.13783
- PMID
- 28317098
- PMCID
- PMC5446571
- NLM abbreviation
- Br J Pharmacol
- ISSN
- 0007-1188
- eISSN
- 1476-5381
- Publisher
- England
- Grant note
- I01 RX002101 / RRD VA R01 NS075599 / NINDS NIH HHS
- Language
- English
- Date published
- 06/2017
- Academic Unit
- Neurology; Molecular Physiology and Biophysics; Iowa Neuroscience Institute; Craniofacial Anomalies Research Center
- Record Identifier
- 9984070228002771
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