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.

Association between gene polymorphisms of voltage-dependent Ca2+ channels and hypertension in the Dai people of China: a case-control study

“…The α1A (CACNA1A) subunit is mainly expressed in the nervous tissue of the brain and involves the transmission of synaptic signals in the central nervous system. Research on rat models has shown that abnormal expression of the CACNA1A gene can lead to the desensitization of calcitonin gene-related peptide (CGRP) receptors, which are critical in maintaining the systolic response of cerebrovascular smooth muscle [27,28]. In addition, Hu Z et al also reported the association between CACNA1A polymorphisms (rs8182538) and hypertension in Chinese Han [15].…”

Basal astrocyte and microglia activation in the central nervous system of Familial Hemiplegic Migraine Type I mice

“…Although an homeostatic role for neuroinflammation has been postulated, it might also lead to further release of pro-inflammatory mediators by surrounding activated glial cells, namely reactive astrocytes and microglia, which in turn may trigger or aggravate an underlying pathological condition [4]. Notably, in primary cultures from from postnatal day 11 trigeminal ganglia tissue (containing a mix of trigeminal ganglion neurons and satellite glial cells) of FHM1 mutant mice, satellite glial cells exhibit an increased release of inflammatory mediators and an up-regulation of specific pro-algogenic receptors [5], but it is questionable whether findings in cultured cells can be translated to the intact trigeminal ganglion as no such increases were observed in isolated trigeminal ganglia from mice that were 11-14 weeks old [6]. In addition, trigeminal infiltration of macrophages was observed, pointing to the development of neuroinflammation in the peripheral nervous system [7].…”

Association between gene polymorphisms of voltage-dependent Ca2+ channels andhypertension in the Dai people of China: a case-control study

“…The α1A (CACNA1A) subunit is mainly expressed in the nervous tissue of the brain and involves the transmission of synaptic signals in the central nervous system. Research on rat models has shown that abnormal expression of the CACNA1A gene can lead to the desensitization of calcitonin gene-related peptide (CGRP) receptors, which are critical in maintaining the systolic response of cerebrovascular smooth muscle[27,28].In addition, Hu Z et al also reported the association between CACNA1A polymorphisms (rs8182538) and hypertension in Chinese Han[15].…”