CGRP receptor activity in mice with global expression of human receptor activity modifying protein 1.
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 AMY1receptor). 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 EC50s. In contrast, cultured trigeminal ganglia from global hRAMP1 mice had a 40-fold leftward shift of the EC50, with similar Rmax values as littermates. In both hRAMP1 cultures, telcagepant blocked CGRP-induced cAMP production, but was not effective in non-transgenic cultures. IC50values 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 AMY1receptors are functional in trigeminal ganglia neurons and vascular smooth muscle.
Department of Molecular Physiology and Biophysics, University of Iowa, Iowa City, IA, USA.
Keegan J
KJ
Bohn
Neuroscience Research Division, Eli Lilly and Company, Lilly Corporate Center, Indianapolis, IN, USA.
Baolin
B
Li
Neuroscience Research Division, Eli Lilly and Company, Lilly Corporate Center, Indianapolis, IN, USA.
Xiaofang
X
Huang
Molecular and Cellular Biology Program, University of Iowa, Iowa City, IA, USA.
Bianca N
BN
Mason
Department of Molecular Physiology and Biophysics, University of Iowa, Iowa City, IA, USA.
Anne-Sophie
AS
Wattiez
Department of Molecular Physiology and Biophysics, University of Iowa, Iowa City, IA, USA.
Adisa
A
Kuburas
Maurice Wilkins Centre and Centre for Brain Research, School of Biological Sciences, University of Auckland, Auckland, New Zealand.
Christopher S
CS
Walker
Quantitative Biology, Eli Lilly and Company, Lilly Corporate Center, Indianapolis, IN, USA.
Peiyi
P
Yang
Quantitative Biology, Eli Lilly and Company, Lilly Corporate Center, Indianapolis, IN, USA.
Jianliang
J
Yu
Quantitative Biology, Eli Lilly and Company, Lilly Corporate Center, Indianapolis, IN, USA.
Beverly A
BA
Heinz
Neuroscience Research Division, Eli Lilly and Company, Lilly Corporate Center, Indianapolis, IN, USA.
Kirk W
KW
Johnson
Department of Molecular Physiology and Biophysics, University of Iowa, Iowa City, IA, USA.|Department of Neurology, University of Iowa, Iowa City, IA, USA.|Molecular and Cellular Biology Program, University of Iowa, Iowa City, IA, USA.|Veterans Affairs Medical Center, Iowa City, IA, USA.
Andrew F
AF
Russo
D000818:Animals; D001381:Azepines / Q000494:pharmacology; D016466:CHO Cells; D000077221:Calcitonin Gene-Related Peptide Receptor Antagonists; D002478:Cells, Cultured; D003412:Cricetulus; D004305:Dose-Response Relationship, Drug; D005260:Female; D020869:Gene Expression Profiling; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D058262:Receptor Activity-Modifying Protein 1 / Q000235:genetics* / Q000378:metabolism; D018015:Receptors, Calcitonin Gene-Related Peptide / Q000378:metabolism*; D013329:Structure-Activity Relationship
D001381:Azepines; D000077221:Calcitonin Gene-Related Peptide Receptor Antagonists; D007093:Imidazoles; D058262:Receptor Activity-Modifying Protein 1; D018015:Receptors, Calcitonin Gene-Related Peptide; C525458:telcagepant