Mining the Nav1.7 interactome: Opportunities for chronic pain therapeutics

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

Research output: Contribution to journalReview article

Abstract

The peripherally expressed voltage-gated sodium NaV1.7 (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, NaV1.7 has been the focus of intense investigation but, to date, no NaV1.7-selective drugs have reached the clinic. Elegant crystallographic studies have demonstrated the potential of designing highly potent and selective NaV1.7 compounds but their therapeutic value remains untested. Transcriptional silencing of NaV1.7 by a naturally expressed antisense transcript has been reported in rodents and humans but whether this represents a viable opportunity for designing NaV1.7 therapeutics is currently unknown. The demonstration that loss of NaV1.7 function is associated with upregulation of endogenous opioids and potentiation of mu- and delta-opioid receptor activities, suggests that targeting only NaV1.7 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 NaV1.7 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 NaV1.7 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 NaV1.7 function in chronic pain.

Original languageEnglish (US)
Pages (from-to)9-20
Number of pages12
JournalBiochemical Pharmacology
Volume163
DOIs
StatePublished - May 1 2019

Fingerprint

Chronic Pain
Opioid Analgesics
Pain
Sodium
Allosteric Regulation
delta Opioid Receptor
Sodium Channels
mu Opioid Receptor
Spinal Ganglia
Synapses
Analgesia
Modulators
Neurons
Neurotransmitter Agents
Analgesics
Rodentia
Spinal Cord
Up-Regulation
Demonstrations
Therapeutics

Keywords

  • Chronic pain
  • Na1.7
  • Non-opioids
  • Novel therapeutics
  • Protein-interactome

ASJC Scopus subject areas

  • Biochemistry
  • Pharmacology

Cite this

Mining the Nav1.7 interactome : Opportunities for chronic pain therapeutics. / Chew, Lindsey A.; Bellampalli, Shreya S.; Dustrude, Erik T.; Khanna, Rajesh.

In: Biochemical Pharmacology, Vol. 163, 01.05.2019, p. 9-20.

Research output: Contribution to journalReview article

Chew, Lindsey A. ; Bellampalli, Shreya S. ; Dustrude, Erik T. ; Khanna, Rajesh. / Mining the Nav1.7 interactome : Opportunities for chronic pain therapeutics. In: Biochemical Pharmacology. 2019 ; Vol. 163. pp. 9-20.
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