Overexpressed NaV1.7 Channels Confer Hyperexcitability to in vitro Trigeminal Sensory Neurons of CaV2.1 Mutant Hemiplegic Migraine Mice

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.

Role of ATP in migraine mechanisms: focus on P2X3 receptors

“…Via cGMP-dependent intracellular pathways, BNP constitutively limits the activity of P2X3 receptors, a process that is largely depressed in the FHM1 phenotype [ 120 ]. In addition, FHM1 mice show upregulation of the Na v 1.7 subtype of voltage gated sodium channel [ 121 ] that contributes to their enhanced excitability.…”

The Expression of Sodium Channel Alpha Subunit (Nav1.7) Receptors in Intracranial Meningioma and Its Comparison to Urothelial, Prostate and Ovarian Cancers

“…epilepsy and chronic pain. The role of these channels in physiological and pathological pathways related to autism, migraine, multiple sclerosis, cancers and immunological disorders has also been known (1). VGSCs increase the action potentials in neurons, monocytes, glial cells and other excitable cells (2).…”