Abstract
The voltage-gated sodium channel Nav1.8 is linked to neuropathic and inflammatory pain, highlighting the potential to serve as a drug target. However, the biophysical mechanisms that regulate Nav1.8 activation and inactivation gating are not completely understood. Progress has been hindered by a lack of biochemical tools for examining Nav1.8 gating mechanisms. Arizona bark scorpion (Centruroides sculpturatus) venom proteins inhibit Nav1.8 and block pain in grasshopper mice (Onychomys torridus). These proteins provide tools for examining Nav1.8 structure–activity relationships. To identify proteins that inhibit Nav1.8 activity, venom samples were fractioned using liquid chromatography (reversed-phase and ion exchange). A recombinant Nav1.8 clone expressed in ND7/23 cells was used to identify subfractions that inhibited Nav1.8 Na+ current. Mass-spectrometry-based bottom-up proteomic analyses identified unique peptides from inhibitory subfractions. A search of the peptides against the AZ bark scorpion venom gland transcriptome revealed four novel proteins between 40 and 60% conserved with venom proteins from scorpions in four genera (Centruroides, Parabuthus, Androctonus, and Tityus). Ranging from 63 to 82 amino acids, each primary structure includes eight cysteines and a “CXCE” motif, where X = an aromatic residue (tryptophan, tyrosine, or phenylalanine). Electrophysiology data demonstrated that the inhibitory effects of bioactive subfractions can be removed by hyperpolarizing the channels, suggesting that proteins may function as gating modifiers as opposed to pore blockers.
Highlights
IntroductionPrimary sensorynociceptive nociceptiveneurons, neurons, whose bodies reside indorsal the dorsal rootPrimary sensory whose cellcell bodies reside in the root ganganglia (DRG)of the body and limbs or in the trigeminal ganglia (TG)of the head and face, glia (DRG) of the body and limbs or in the trigeminal ganglia (TG) of the head and face, transmit system (CNS) (CNS) [1,2,3,4]. [1,2,3,4]
Lyophilized bark scorpion venom samples weresamples were hydrated in 0.1% trifluoroacetic in water andby fractionated by reversed-phase liquid hydrated in 0.1%
These results suggest thatThese bark scorpion venom that proteins
Summary
IntroductionPrimary sensorynociceptive nociceptiveneurons, neurons, whose bodies reside indorsal the dorsal rootPrimary sensory whose cellcell bodies reside in the root ganganglia (DRG)of the body and limbs or in the trigeminal ganglia (TG)of the head and face, glia (DRG) of the body and limbs or in the trigeminal ganglia (TG) of the head and face, transmit system (CNS) (CNS) [1,2,3,4]. [1,2,3,4]. Neurons, whose bodies reside indorsal the dorsal root. Primary sensory whose cellcell bodies reside in the root ganganglia (DRG). Of the body and limbs or in the trigeminal ganglia (TG). Of the head and face, glia (DRG) of the body and limbs or in the trigeminal ganglia (TG) of the head and face, transmit system (CNS) (CNS) [1,2,3,4]. Tissuedamage damagedue duetoto transmit pain pain signals signals to to the the central central nervous nervous system injury, aging, or disease causes biochemical changes in nociceptive neurons that activate injury, aging, or disease causes biochemical changes in nociceptive neurons that activate the Actithevoltage-gated voltage-gatedsodium sodiumchannel channel(VGSC). (VGSC)Nav1.7, Nav1.7,which whichthen thenrecruits recruitsNav1.8 Nav1.8 [1,5,6,7,8].
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