Anxiety and dysautonomia symptoms in patients with a NaV1.7 mutation and the potential benefits of low-dose short-acting guanfacine.

PURPOSE: Guanfacine is an α2A-adrenergic receptor agonist, FDA-approved to treat attention-deficit hyperactivity disorder and high blood pressure, typically as an extended-release formulation up to 7 mg/day. In our dysautonomia clinic, we observed that off-label use of short-acting guanfacine at 1 mg/day facilitated symptom relief in two families with multiple members presenting with severe generalized anxiety. We also noted anecdotal improvements in associated dysautonomia symptoms such as hyperhidrosis, cognitive impairment, and palpitations. We postulated that a genetic deficit existed in these patients that might augment guanfacine susceptibility. METHODS: We used whole-exome sequencing to identify mutations in patients with shared generalized anxiety and dysautonomia symptoms. Guanfacine-induced changes in the function of voltage-gated Na+ channels were investigated using voltage-clamp electrophysiology. RESULTS: Whole-exome sequencing uncovered the p.I739V mutation in SCN9A in the proband of two nonrelated families. Moreover, guanfacine inhibited ionic currents evoked by wild-type and mutant NaV1.7 encoded by SCN9A, as well as other NaV channel subtypes to a varying degree. CONCLUSION: Our study provides further evidence for a possible pathophysiological role of NaV1.7 in anxiety and dysautonomia. Combined with off-target effects on NaV channel function, daily administration of 1 mg short-acting guanfacine may be sufficient to normalize NaV channel mutation-induced changes in sympathetic activity, perhaps aided by partial inhibition of NaV1.7 or other channel subtypes. In a broader context, expanding genetic and functional data about ion channel aberrations may enable the prospect of stratifying patients in which mutation-induced increased sympathetic tone normalization by guanfacine can support treatment strategies for anxiety and dysautonomia symptoms.

N-Type Inactivation Variances in Honeybee and Asian Giant Hornet Kv Channels.

Background: With the emergence of the Asian giant hornet as a threat to honeybee survival, knowledge of potential ion channel targets expressed in the nervous system can propel the development of new insecticides that are safe for pollinators. We therefore examined the biophysical properties of the Shaker-like voltage-gated potassium (Kv) channel of Apis mellifera (AmKv1; Western honeybee) and Vespa mandarinia (VmKv1; Asian giant hornet) and compared these data with isoforms that differ in N-terminal amino acid sequence. Methods: We expressed AmKv1 and VmKv1 in Xenopus laevis oocytes and determined their gating characteristics using electrophysiological measurements. Resulting features were compared with those gleaned from N-terminal isoforms. Results: AmKv1 generates large potassium currents, but lacks an extended N-terminal region and therefore rapid N-type inactivation, as originally described in Shaker channels. Of its seven isoforms, two have a long N-tail and subsequently display inactivation. Notably, the isoform with the lengthiest N-terminal region only partially inactivates. VmKv1 potassium currents display N-type inactivation, as expected with an extended N-tail. One isoform shows an enhanced inactivation rate, whereas currents from another isoform with a substantially different N-terminal sequence could not be measured. Conclusion: AmKv1 and VmKv1 are functional Kv channels with strikingly different gating properties. Due to the presence of an extended N-terminal region, VmKv1 inactivates rapidly, whereas AmKv1 does not possess these residues and N-type inactivation is absent. Remarkably, virtually all isoforms of AmKv1 lack fast inactivation, whereas all studied VmKv1 isoforms inactivate, thereby suggesting a functional divergence that may be exploited for insecticide design.