Animal Toxins Can Alter the Function of Nav1.8 and Nav1.9

Abstract

Human voltage-activated sodium (Nav) channels are adept at rapidly transmitting electrical signals across long distances in various excitable tissues. As such, they are amongst the most widely targeted ion channels by drugs and animal toxins. Of the nine isoforms, Nav1.8 and Nav1.9 are preferentially expressed in DRG neurons where they are thought to play an important role in pain signaling. Although the functional properties of Nav1.8 have been relatively well characterized, difficulties with expressing Nav1.9 in established heterologous systems limit our understanding of the gating properties and toxin pharmacology of this particular isoform. This review summarizes our current knowledge of the role of Nav1.8 and Nav1.9 in pain perception and elaborates on the approaches used to identify molecules capable of influencing their function.

Scorpion toxin peptide action at the ion channel subunit level

“…Our analysis indicates that the number of studies prioritising the identification of specific molecular targets using isolated and well-defined peptide fragments has steadily increased overtime. The development of recent techniques such as site-directed mutagenesis, production of recombinant toxin variants and chimeric ion channel constructs, together with use of improved 3D modelling, has allowed greater understanding of toxin-channel interactions and the underlying mechanisms determining the SCTX selectivity and affinity (Gilchrist and Bosmans, 2012;Zhang et al, 2011Zhang et al, , 2012Gur et al, 2011;Gurevitz, 2012;Ma et al, 2013). Use of cloned ion channels within expression systems has been central to study of SCTX peptide action.…”

“…AmmVIII and AaH1 were found not to alter the Nav1.9 current in DRG neurons (Abbas et al, 2013). Recent publications have suggested that Tityus bahiensis scorpion venom (TbScV) (Moraes et al, 2011) and TsVII (Tityus serrulatus) (Gilchrist and Bosmans, 2012) have potential action on Nav1.8 and Nav1.9 channels, although this requires further assessment and characterization.…”

“…Previous reviews have focused on the structural, computational, and molecular analysis of scorpion venom components and ion channel interactions (Smith et al, 2014;Gurevitz et al, 2014), as well as functional comparison of their actions on ion channels. Although some reviews have outlined a broad overview of SCTX peptide action Quintero-Hernandez et al, 2013;du Plessis et al, 2008), the majority have provided relatively detailed information of SCTX action within particular ion channel subfamilies, such as sodium channels Gordon et al, 2007;Pedraza Escalona and Possani, 2013;Pucca et al, 2015a;Gilchrist and Bosmans, 2012;Gordon and Gurevitz, 2003), potassium channels MartinEauclaire and Bougis, 2012;Jimenez-Vargas et al, 2012a;Bartok et al, 2015;Yu et al, 2016;Bougis and Martin-Eauclaire, 2015;Yang et al, 2015;Wang et al, 2014;Wanke and Restano-Cassulini, 2007), and to a lesser extent, calcium Norton and McDonough, 2008;Ramos-Franco and Fill, 2016), and chloride channels Dardevet et al, 2015). This review establishes a comprehensive comparison of the broad range of functionally-validated SCTX peptide actions across the breadth of ion channel families.…”

Animal Venom Components: New Approaches for Pain Treatment

“…Toxins isolated from the venom of Thrixopelma pruriens, Ceratogyrus cornuatus and Phrixotrichus auratus constitute very promising molecules since they are reported to inhibit the different subtypes of voltage gated sodium channels (Nav): Nav1.7 and Nav1.8 [16,17]. These subtypes of channels are related to pain signaling, since they are selectively expressed in peripheral sensory neurons and contribute for the transmission of the pain signal [18]. In addition, toxins which block voltage gated calcium channels may induce anti-nociception and are found in the venom of Selenocosmia huwena, Grammostola rosea, Agelenopsis aperta and Phoneutria nigriventer [5,13,14,19,20].…”

Venom: the sharp end of pain therapeutics

“…8 Na V 1.9 is also a desirable drug target (as shown using mouse models) and is also expressed in DRG neurons but has proved difficult to functionally express in heterologous systems and is therefore challenging to study. 9 TRPV1 (a member of the TRP superfamily of excitatory ion channels that bind vanilloids) is predominantly expressed by nociceptors and is therefore also a popular pain relief target, 10 but in clinical trials, drugs inhibiting the TRPV1 channel cause hyperthermia and decreased sensitivity to painful levels of heat. To overcome these life-threatening side effects, Fischer et al, 11 developed tools to block phosphorylation of TRPV1 instead of blocking the channel: this is effective through the disruption of TRPV1 interaction with A-kinase anchoring protein 79 (AKAP79).…”