Nav1.7: Stress-Induced Changes in Immunoreactivity within Magnocellular Neurosecretory Neurons of the Supraoptic Nucleus

Joel A Black,Janneke Gj Hoeijmakers,Catharina G Faber,Ingemar Sj Merkies,Stephen G Waxman

doi:10.1186/1744-8069-9-39

Abstract

BackgroundNaV1.7 is preferentially expressed, at relatively high levels, in peripheral neurons, and is often referred to as a “peripheral” sodium channel, and NaV1.7-specific blockers are under study as potential pain therapeutics which might be expected to have minimal CNS side effects. However, occasional reports of patients with NaV1.7 gain-of-function mutations and apparent hypothalamic dysfunction have appeared. The two sodium channels previously studied within the rat hypothalamic supraoptic nucleus, NaV1.2 and NaV1.6, display up-regulated expression in response to osmotic stress.ResultsHere we show that NaV1.7 is present within vasopressin-producing neurons and oxytocin-producing neurons within the rat hypothalamus, and demonstrate that the level of Nav1.7 immunoreactivity is increased in these cells in response to osmotic stress.ConclusionsNaV1.7 is present within neurosecretory neurons of rat supraoptic nucleus, where the level of immunoreactivity is dynamic, increasing in response to osmotic stress. Whether NaV1.7 levels are up-regulated within the human hypothalamus in response to environmental factors or stress, and whether NaV1.7 plays a functional role in human hypothalamus, is not yet known. Until these questions are resolved, the present findings suggest the need for careful assessment of hypothalamic function in patients with NaV1.7 mutations, especially when subjected to stress, and for monitoring of hypothalamic function as NaV1.7 blocking agents are studied.

Highlights

NaV1.7 is preferentially expressed, at relatively high levels, in peripheral neurons, and is often referred to as a “peripheral” sodium channel, and NaV1.7-specific blockers are under study as potential pain therapeutics which might be expected to have minimal CNS side effects
We have built upon earlier studies in rodents which showed that the deployment of sodium channels in the hypothalamus is dynamic, with levels of expression of the two sodium channel subtypes that were previously studied, NaV1.2 and NaV1.6, and of sodium channel beta-1 and beta-2 subunits and sodium currents, displaying upregulation within supraoptic magnocellular neurons exposed to osmotic stress via salt-loading [24] and as a result of the hyperosmolar state associated with experimental diabetes [25]
Previous work from our laboratory has demonstrated the expression of the tetrodotoxin-sensitive (TTX-S) sodium channels, NaV1.2 and NaV1.6, but not NaV1.1 and NaV1.3, and of TTX-S sodium currents in magnocellular neurosecretory cells (MSC) of the hypothalamic supraoptic nucleus [24]

Summary

Introduction

NaV1.7 is preferentially expressed, at relatively high levels, in peripheral neurons, and is often referred to as a “peripheral” sodium channel, and NaV1.7-specific blockers are under study as potential pain therapeutics which might be expected to have minimal CNS side effects. The two sodium channels previously studied within the rat hypothalamic supraoptic nucleus, NaV1.2 and NaV1.6, display up-regulated expression in response to osmotic stress. The occurrence of SIADH in this patient suggested the possibility that the gain-of -function mutation in NaV1.7 might have contributed to hyperexcitability of vasopressin-releasing (magnocellular neurosecretory) neurons in the supraoptic nucleus within the hypothalamus. We have built upon earlier studies in rodents which showed that the deployment of sodium channels in the hypothalamus is dynamic, with levels of expression of the two sodium channel subtypes that were previously studied, NaV1.2 and NaV1.6, and of sodium channel beta-1 and beta-2 subunits and sodium currents, displaying upregulation within supraoptic magnocellular neurons exposed to osmotic stress via salt-loading [24] and as a result of the hyperosmolar state associated with experimental diabetes [25]. We demonstrate here that NaV1.7 is present within vasopressin- and oxytocin-producing neurons of the supraoptic nucleus, and show that the level of NaV1.7 protein in these cells in not static but, on the contrary, is increased in response to salt-loading

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