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

Kayi Y. Chan; Alejandro Labastida-Ramírez; Martha B. Ramírez-Rosas; Sieneke Labruijere; Ingrid M. Garrelds; Alexander H.J. Danser; Arn M.J.M. van den Maagdenberg; Antoinette MaassenVanDenBrink

doi:10.1177/0271678X17725673

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

Kayi Y. Chan, Alejandro Labastida-Ramírez, Martha B. Ramírez-Rosas, Sieneke Labruijere, Ingrid M. Garrelds, Alexander H.J. Danser, Arn M.J.M. van den Maagdenberg, Antoinette MaassenVanDenBrink^*

^*Corresponding author for this work

Wolfson SPaRC

Research output: Contribution to journal › Article › peer-review

12 Citations (Scopus)

Abstract

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.

Original language	English
Pages (from-to)	718-729
Number of pages	12
Journal	Journal of Cerebral Blood Flow and Metabolism
Volume	39
Issue number	4
DOIs	https://doi.org/10.1177/0271678X17725673
Publication status	Published - 1 Apr 2019

Keywords

Calcitonin gene-related peptide
migraine
R192Q
trigeminovascular
vasodilation

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10.1177/0271678X17725673

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Chan, K. Y., Labastida-Ramírez, A., Ramírez-Rosas, M. B., Labruijere, S., Garrelds, I. M., Danser, A. H. J., van den Maagdenberg, A. M. J. M., & MaassenVanDenBrink, A. (2019). Trigeminovascular calcitonin gene-related peptide function in Cacna1a R192Q-mutated knock-in mice. Journal of Cerebral Blood Flow and Metabolism, 39(4), 718-729. https://doi.org/10.1177/0271678X17725673

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title = "Trigeminovascular calcitonin gene-related peptide function in Cacna1a R192Q-mutated knock-in mice",

abstract = "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.",

keywords = "Calcitonin gene-related peptide, migraine, R192Q, trigeminovascular, vasodilation",

author = "Chan, {Kayi Y.} and Alejandro Labastida-Ram{\'i}rez and Ram{\'i}rez-Rosas, {Martha B.} and Sieneke Labruijere and Garrelds, {Ingrid M.} and Danser, {Alexander H.J.} and {van den Maagdenberg}, {Arn M.J.M.} and Antoinette MaassenVanDenBrink",

note = "Funding Information: The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This work was supported by grants of the Netherlands Organization for Scientific Research (to A. Maassen VanDenBrink; Vidi grant nr. 917.11.349) and the Center of Medical System Biology established by the Netherlands Genomics Initiative/Netherlands Organisation for Scientific Research (to A.M.J.M. van den Maagdenberg; EU-funded FP7 {\textquoteleft}{\textquoteleft}EUROHEADPAIN{\textquoteright}{\textquoteright} grant nr. 6026337). Publisher Copyright: {\textcopyright} The Author(s) 2017.",

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doi = "10.1177/0271678X17725673",

language = "English",

volume = "39",

pages = "718--729",

journal = "Journal of Cerebral Blood Flow and Metabolism",

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T1 - Trigeminovascular calcitonin gene-related peptide function in Cacna1a R192Q-mutated knock-in mice

AU - Chan, Kayi Y.

AU - Labastida-Ramírez, Alejandro

AU - Ramírez-Rosas, Martha B.

AU - Labruijere, Sieneke

AU - Garrelds, Ingrid M.

AU - Danser, Alexander H.J.

AU - van den Maagdenberg, Arn M.J.M.

AU - MaassenVanDenBrink, Antoinette

N1 - Funding Information: The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This work was supported by grants of the Netherlands Organization for Scientific Research (to A. Maassen VanDenBrink; Vidi grant nr. 917.11.349) and the Center of Medical System Biology established by the Netherlands Genomics Initiative/Netherlands Organisation for Scientific Research (to A.M.J.M. van den Maagdenberg; EU-funded FP7 ‘‘EUROHEADPAIN’’ grant nr. 6026337). Publisher Copyright: © The Author(s) 2017.

PY - 2019/4/1

Y1 - 2019/4/1

N2 - 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.

AB - 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.

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

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