Abstract
Trigeminal sensory neurons of transgenic knock-in (KI) mice expressing the R192Q missense mutation in the α1A subunit of neuronal voltage-gated CaV2.1 Ca2+ channels, which leads to familial hemiplegic migraine type 1 (FHM1) in patients, exhibit a hyperexcitability phenotype. Here, we show that the expression of NaV1.7 channels, linked to pain states, is upregulated in KI primary cultures of trigeminal ganglia (TG), as shown by increased expression of its α1 subunit. In the majority of TG neurons, NaV1.7 channels are co-expressed with ATP-gated P2X3 receptors (P2X3R), which are important nociceptive sensors. Reversing the trigeminal phenotype with selective CaV2.1 channel inhibitor ω-agatoxin IVA inhibited NaV1.7 overexpression. Functionally, KI neurons revealed a TTX-sensitive inward current of larger amplitude that was partially inhibited by selective NaV1.7 blocker Tp1a. Under current-clamp condition, Tp1a raised the spike threshold of both wild-type (WT) and KI neurons with decreased firing rate in KI cells. NaV1.7 activator OD1 accelerated firing in WT and KI neurons, a phenomenon blocked by Tp1a. Enhanced expression and function of NaV1.7 channels in KI TG neurons resulted in higher excitability and facilitated nociceptive signaling. Co-expression of NaV1.7 channels and P2X3Rs in TGs may explain how hypersensitivity to local stimuli can be relevant to migraine.
Highlights
Familial hemiplegic migraine type 1 (FHM1) is an autosomal dominant subtype of migraine with aura (IHS, 2013), with similar clinical features (Thomsen et al, 2002)–apart from the hemiparesis–and trigger factors (Hansen et al, 2011) as observed for the common forms of migraine
NaV 1.7 Channels in Migraine Mice hemiplegic migraine (Ophoff et al, 1996), in the orthologous mouse Cacna1a gene resulted in a transgenic FHM1 R192Q knock-in (“R192Q KI”) mouse model that expresses key features of migraine pathophysiology and was instrumental in unraveling mechanisms of migraine pathophysiology (Ferrari et al, 2015; Pietrobon and Brennan, 2019)
Since P2X3 receptors (P2X3R)-expressing neurons are important contributors to trigeminal pain (Wirkner et al, 2005; Burnstock, 2006), we investigated whether P2X3R immunoreactivity was coexpressed with NaV 1.7 α1 immunopositivity
Summary
Familial hemiplegic migraine type 1 (FHM1) is an autosomal dominant subtype of migraine with aura (IHS, 2013), with similar clinical features (Thomsen et al, 2002)–apart from the hemiparesis–and trigger factors (Hansen et al, 2011) as observed for the common forms of migraine. The hyperexcitability state of KI TG neurons is shown by a lower firing threshold (Fioretti et al, 2011; Hullugundi et al, 2014; Marchenkova et al, 2016a) suggesting that differences in subthreshold conductances, which can facilitate the voltage trajectory to spike discharge, increase the probability to reach the action potential (AP) threshold (Dib-Hajj et al, 2013) Such function can be attributed to various subtypes of subthreshold voltage-gated NaV Na+ currents (Raman and Bean, 1997; Ogata et al, 2001), some of which are expressed by primary sensory neurons and have been associated with pathological pain conditions (Toledo-Aral et al, 1997; Wood et al, 2004; Dib-Hajj et al, 2010; Habib et al, 2015). We here characterized the expression and function of NaV 1.7 channels in WT and R192Q KI TG neurons to explore their contribution to the enhanced neuronal excitability seen in KI TG neurons, which may have relevance to understanding migraine pathophysiology
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