Pharmacology of the Nav1.1 domain IV voltage sensor reveals coupling between inactivation gating processes

Jeremiah D. Osteen, Kevin Sampson, Vivek Iyer, David Julius, Frank Bosmans

Research output: Contribution to journalArticlepeer-review


The Nav1.1 voltage-gated sodium channel is a critical contributor to excitability in the brain, where pathological loss of function leads to such disorders as epilepsy, Alzheimer's disease, and autism. This voltage-gated sodium (Nav) channel subtype also plays an important role in mechanical pain signaling by primary afferent somatosensory neurons. Therefore, pharmacologic modulation of Nav1.1 represents a potential strategy for treating excitability disorders of the brain and periphery. Inactivation is a complex aspect of Nav channel gating and consists of fast and slow components, each of which may involve a contribution from one or more voltage-sensing domains. Here, we exploit the Hm1a spider toxin, a Nav1.1-selective modulator, to better understand the relationship between these temporally distinct modes of inactivation and ask whether they can be distinguished pharmacologically. We show that Hm1a inhibits the gating movement of the domain IV voltage sensor (VSDIV), hindering both fast and slow inactivation and leading to an increase in Nav1.1 availability during high-frequency stimulation. In contrast, ICA-121431, a small-molecule Nav1.1 inhibitor, accelerates a subsequent VSDIV gating transition to accelerate entry into the slow inactivated state, resulting in use-dependent block. Further evidence for functional coupling between fast and slow inactivation is provided by a Nav1.1mutant inwhich fast inactivation removal has complex effects on slow inactivation. Taken together, our data substantiate the key role of VSDIV in Nav channel fast and slow inactivation and demonstrate that these gating processes are sequential and coupled through VSDIV. These findings provide insight into a pharmacophore on VSDIV through which modulation of inactivation gating can inhibit or facilitate Nav1.1 function.

Original languageEnglish (US)
Pages (from-to)6836-6841
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Issue number26
StatePublished - Jun 27 2017


  • Fast inactivation
  • Hm1a spider toxin
  • ICA-121431
  • Nav1.1
  • Slow inactivation

ASJC Scopus subject areas

  • General


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