Structural basis of venom peptides that inhibit a Na+ channel regulator of pain

NIH RePORTER · NIH · P20 · $151,287 · view on reporter.nih.gov ↗

Abstract

Chronic pain and opioid abuse cause human suffering and impose a burden on public health systems. A better understanding of the mechanisms that block transmission of pain signals would advance efforts to develop non-addictive pain drugs. Pain-pathway neurons transmit signals to the brain via action potentials. The voltage-gated sodium channel (VGSC) Nav1.8 is a protein pore that regulates the flux of Na+ across the membranes of nociceptive neurons, producing the action potentials that carry pain signals to the brain. Injury, aging and disease cause biochemical changes in neurons that activate Nav1.8 to initiate action potentials. Inactivation of Nav1.8 halts the transmission of pain signals. The mechanisms that govern inactivation provide a strategy for developing non-addictive pain drugs. Venom peptides from scorpions provide a toolkit for investigating inactivation mechanisms. For example, cryo-electron microscopy studies using scorpion peptides bound to Nav1.7, a channel responsible for spontaneous pain disorders, revealed the structural basis of fast inactivation. However, studying Nav1.8 inactivation mechanisms has proved challenging. While Nav1.8 has been linked to neuropathic and inflammatory pain, highlighting the potential for Nav1.8 to serve as an alternative drug target to Nav1.7, the mechanisms that regulate inactivation are not completely understood. Progress has been hindered by a lack of venom peptides that modify Nav1.8 gating. Arizona bark scorpion venom inhibits Nav1.8 and blocks pain in species of predatory mice. This study will use computational modeling to predict docking trajectories between inhibitory peptides and Nav1.8. The structural basis for peptide inhibition of Nav1.8 will be characterized by 1) mapping binding sites between peptides and the channel, and 2) building computational models of the peptide-Nav1.8 complex. Computational models of peptide-bound channels will reveal the structural basis for Nav1.8 gating. These goals are significant because inactivation is critical for regulating Nav1.8 activity and pain signal transmission. Knowledge of the biophysical and molecular bases for peptide-mediated inhibition of Nav1.8 would provide structural guides for engineering non-addictive pain drugs.

Key facts

NIH application ID
10415506
Project number
5P20GM103640-10
Recipient
UNIVERSITY OF OKLAHOMA
Principal Investigator
ASHLEE Hedgecock ROWE
Activity code
P20
Funding institute
NIH
Fiscal year
2021
Award amount
$151,287
Award type
5
Project period
2021-06-01 → 2023-05-31