Trigeminovascular calcitonin gene-related peptide function in Cacna1a R192Q-mutated knock-in mice

Familial hemiplegic migraine type 1 (FHM1) is a rare migraine subtype. Whereas transgenic knock-in mice with the human pathogenic FHM1 R192Q missense mutation in the Cacna1a gene reveal overall neuronal hyperexcitability, the effects on the trigeminovascular system and calcitonin gene-related peptid...

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Published in:Journal of cerebral blood flow and metabolism 2019-04, Vol.39 (4), p.718-729
Main Authors: Chan, Kayi Y, Labastida-Ramírez, Alejandro, Ramírez-Rosas, Martha B, Labruijere, Sieneke, Garrelds, Ingrid M, Danser, Alexander HJ, van den Maagdenberg, Arn MJM, MaassenVanDenBrink, Antoinette
Format: Article
Language:English
Subjects:
Animals
Calcitonin Gene-Related Peptide - genetics
Calcitonin Gene-Related Peptide - metabolism
Calcium Channels, N-Type - genetics
Cerebellar Ataxia - genetics
Gene Knock-In Techniques
Humans
Mice
Migraine Disorders - genetics
Mutation, Missense
Original
Peripheral Vascular Diseases
Trigeminal Ganglion - chemistry
Vasodilation
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Summary:Familial hemiplegic migraine type 1 (FHM1) is a rare migraine subtype. Whereas transgenic knock-in mice with the human pathogenic FHM1 R192Q missense mutation in the Cacna1a gene reveal overall neuronal hyperexcitability, the effects on the trigeminovascular system and calcitonin gene-related peptide (CGRP) receptor are largely unknown. This gains relevance as blockade of CGRP and its receptor are therapeutic targets under development. Hence, we set out to test these effects in FHM1 mice. We characterized the trigeminovascular system of wild-type and FHM1 mice through: (i) in vivo capsaicin- and CGRP-induced dural vasodilation in a closed-cranial window; (ii) ex vivo KCl-induced CGRP release from isolated dura mater, trigeminal ganglion and trigeminal nucleus caudalis; and (iii) peripheral vascular function in vitro. In mutant mice, dural vasodilatory responses were significantly decreased compared to controls. The ex vivo release of CGRP was not different in the components of the trigeminovascular system between genotypes; however, sumatriptan diminished the release in the trigeminal ganglion, trigeminal nucleus caudalis and dura mater but only in wild-type mice. Peripheral vascular function was similar between genotypes. These data suggest that the R192Q mutation might be associated with trigeminovascular CGRP receptor desensitization. Novel antimigraine drugs should be able to revert this complex phenomenon.
ISSN:0271-678X
1559-7016
DOI:10.1177/0271678X17725673