Mining the Na v 1.7 interactome: Opportunities for chronic pain therapeutics

Lindsey A. Chew, Shreya S. Bellampalli, Erik T. Dustrude, Rajesh Khanna

Research output: Contribution to journalReview article

1 Scopus citations

Abstract

The peripherally expressed voltage-gated sodium Na V 1.7 (gene SCN9A) channel boosts small stimuli to initiate firing of pain-signaling dorsal root ganglia (DRG) neurons and facilitates neurotransmitter release at the first synapse within the spinal cord. Mutations in SCN9A produce distinct human pain syndromes. Widely acknowledged as a “gatekeeper” of pain, Na V 1.7 has been the focus of intense investigation but, to date, no Na V 1.7-selective drugs have reached the clinic. Elegant crystallographic studies have demonstrated the potential of designing highly potent and selective Na V 1.7 compounds but their therapeutic value remains untested. Transcriptional silencing of Na V 1.7 by a naturally expressed antisense transcript has been reported in rodents and humans but whether this represents a viable opportunity for designing Na V 1.7 therapeutics is currently unknown. The demonstration that loss of Na V 1.7 function is associated with upregulation of endogenous opioids and potentiation of mu- and delta-opioid receptor activities, suggests that targeting only Na V 1.7 may be insufficient for analgesia. However, the link between opioid-dependent analgesic mechanisms and function of sodium channels and intracellular sodium-dependent signaling remains controversial. Thus, additional new targets – regulators, modulators – are needed. In this context, we mine the literature for the known interactome of Na V 1.7 with a focus on protein interactors that affect the channel's trafficking or link it to opioid signaling. As a case study, we present antinociceptive evidence of allosteric regulation of Na V 1.7 by the cytosolic collapsin response mediator protein 2 (CRMP2). Throughout discussions of these possible new targets, we offer thoughts on the therapeutic implications of modulating Na V 1.7 function in chronic pain.

Original languageEnglish (US)
Pages (from-to)9-20
Number of pages12
JournalBiochemical Pharmacology
Volume163
DOIs
StatePublished - May 2019

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Keywords

  • Chronic pain
  • Na 1.7
  • Non-opioids
  • Novel therapeutics
  • Protein-interactome

ASJC Scopus subject areas

  • Biochemistry
  • Pharmacology

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