Voltage-gated sodium channel impairing toxin ~ VenomZone

Channel Voltage-gated sodium channels (Nav) are the trademark of electro-excitable cells, carrying the fast transient inward sodium current during the depolarization phase of an action potential. They consist of a ~260-kDa pore-forming α-subunit associated with auxiliary β-subunits of ~30 kDa (β1β4 for mammalian and tipE for insect Nav channels). The α-subunit contains four homologous but non-identical repeats (DI-DIV), enclosing the ion conduction pore (Fig.1). Each of these four repeats consists of six membrane-spanning segments (S1-S6). The first four segments (S1-S4) of each repeat comprise the voltage sensor domain, with highly conserved positively charged amino acid residues (Arg or Lys) in the S4 segment serving as gating charges. The four positively charged S4 segments are thought to move outward through the membrane in response to depolarization, changing the channel conformation and thereby opening the ion conduction pathway to generate a transient sodium current. The exact mechanism underlying the gating process is poorly understood. Segments S5 and S6 from all four repeats surround the pore of the channel, with the extracellular linker between S5 and S6 dipping back into the membrane to form the ion selectivity filter (Catterall et al., 2007).

Figure 1: Neurotoxin receptor sites on voltage-gated sodium channels. Sites 1-5 are represented, whereas site 6 is not represented. This site has not been studied in details and probably overlaps at least partially with site 3 (Reprinted from Toxicon, Catterall et al., 2007, © 2007, with permission from Elsevier.)

Mammals have nine isoforms of the α-subunit of Nav1, the subunit containing both the sodium-conducting pore and voltage-sensing gate. The nine mammalian Nav1 isoforms can be categorized into those that are TTX-sensitive versus those that are resistant, with Kd or IC(50) values in the nM versus μM ranges, respectively. Two, Nav1.8 and Nav1.9, are found in primary sensory neurons and are highly resistant to TTX (indicated as ^R in the table below). One, Nav1.5, found in cardiac muscle, is moderately TTX resistant, and the remaining six Nav1 isoforms are exquisitely sensitive to TTX ( ^S in the table below). One of these, Nav1.4 is found exclusively in skeletal muscle. Presently, the five neuronal subtypes that are TTX-sensitive (i.e., Nav1.1, 1.2, 1.3, 1.6, and 1.7) cannot be readily functionally differentiated in native systems (Wilson et al., 2011).

The β-subunit has a single membrane-spanning segment, with a large extracellular and small intracellular domain, and regulates the expression and trafficking of the α-subunit as well as modulating its voltage sensitivity. Navβ2 and β4 are covalently linked to the α-subunit via a disulfide bond, whereas Navβ1 and β3 are non-covalently linked (Zhang et al., 2013).

Toxin

	Nav channels	Toxins from different taxa that target Nav channels. Click on to retrieve channels or toxins of interest.
	Human	Snake	Scorpion	Cone snail	Spider	Cnidarian	Insect	Other	All
Nav1.1/SCN1A ^S		-
Nav1.2/SCN2A ^S		-
Nav1.3/SCN3A ^S		-						-
Nav1.4/SCN4A ^S							-	-
Nav1.5/SCN5A ^R		-					-	-
Nav1.6/SCN8A ^S		-					-
Nav1.7/SCN9A ^S		-
Nav1.8/SCN10A ^R								-
Nav1.9/SCN11A ^R		-		-		-		-
Nav all
	Drosophila	Snake	Scorpion	Cone snail	Spider	Cnidarian	Insect	Other	All
DmNav1/para		-		-				-

Peptide toxins from venomous animals can bind to at least four Nav receptor sites (Fig.1). Site 1 is located on the extracellular mouth of the channel and is targeted by a few peptide toxins, including μ-conotoxins and probably some spider toxins such as hainantoxins-1 and 3-5 and huwentoxin-4. These peptides are thought to act as a plug, physically blocking the pore of the Nav channel. Receptor sites 3, 4, and 6 are targeted by peptide toxins that modulate channel gating rather than blocking the pore of the channel. Scorpion α-toxins typically target site 3, together with some sea anemone and spider toxins, including Magi-4 and δ-atracotoxins. These site 3 toxins slow or inhibit the inactivation process of Nav channels. Scorpion β-toxins are known as the classic site 4 toxins and cause a hyperpolarizing shift of the activation of the Nav channel. Some spider toxins like Magi-5 and δ-palutoxins-IT are also reported to bind to site 4. Finally, site 6 is targeted by δ-conotoxins that slow the inactivation of Nav channels upon binding similar to site 3 toxins. Site 6 has not been studied in detail and probably overlaps at least partially with site 3 (Billen et al., 2010). Moreover, some peptide toxins, such as μO-conotoxins and ι-conotoxins, may target receptor sites distinct from those described. μO-conotoxins seem to interfere with the voltage sensors in domain II of Nav to restrict channel opening, while ι-conotoxins activate Nav, but unlike δ-conotoxins, do this without significantly affecting inactivation (Lewis et al., 2012 and Knapp et al., 2012).

Voltage-gated sodium channel impairing toxin

Venom protein entries in UniProtKB/Swiss-Prot

Acanthoscurria gomesiana (Tarantula spider) (Phormictopus pheopygus)

Acanthoscurria natalensis (Tarantula spider)

Acanthoscurria paulensis (Brazilian giant black tarantula spider)

Actinia equina (Beadlet anemone)

Agelena orientalis (Funnel-web spider)

Agelenopsis aperta (North American funnel-web spider) (Agelenopsis gertschi)

Ancylometes sp. (South American fishing spider)

Androctonus amoreuxi (African fattail scorpion) (Scorpio amoreuxi)

Androctonus australis (Sahara scorpion)

Androctonus crassicauda (Arabian fat-tailed scorpion)

Androctonus mauritanicus mauritanicus (Scorpion)

Anemonia erythraea (Sea anemone)

Anemonia sulcata (Mediterranean snakelocks sea anemone)

Anemonia viridis (Snakelocks anemone)

Anoplius samariensis (Solitary wasp)

Antheopsis maculata (Sea anemone)

Anthopleura elegantissima (Green aggregating anemone) (Actinia elegantissima)

Anthopleura fuscoviridis (Sea anemone)

Anthopleura sp. (strain 'Zhanjiang') (Sea anemone)

Anthopleura xanthogrammica (Giant green sea anemone) (Actinia xanthogrammica)

Anuroctonus phaiodactylus (Mafia scorpion)

Apomastus schlingeri (Trap-door spider) (Aptostichus schlingeri)

Atrax robustus (Sydney funnel-web spider)

Augacephalus ezendami (Mozambique baboon spider) (Ceratogyrus ezendami)

Babycurus centrurimorphus (East African scorpion)

Batozonellus maculifrons (Solitary wasp)

Brachypelma smithi (Mexican red knee tarantula) (Eurypelma smithi)

Bumba pulcherrimaklaasi (Tarantula spider) (Euathlus pulcherrimaklaasi)

Bunodosoma caissarum (Sea anemone)

Bunodosoma cangicum (Sea anemone)

Bunodosoma capense (Knobbly sea anemone) (Actinia capensis)

Bunodosoma granuliferum (Red warty sea anemone)

Buthacus arenicola (North African scorpion)

Buthacus leptochelys (Egyptian fat-tailed scorpion) (Androctonus leptochelys)

Buthacus macrocentrus (Turkish scorpion)

Buthus israelis (Israeli scorpion) (Buthus occitanus israelis)

Buthus occitanus mardochei (Moroccan scorpion) (Buthus mardochei)

Buthus occitanus tunetanus (Common European scorpion) (Buthus tunetanus)

Californiconus californicus (California cone) (Conus californicus)

Calliactis parasitica (Sea anemone) (Actinia parasitica)

Calliophis bivirgatus (Blue Malaysian coral snake) (Maticora bivirgata)

Centruroides baergi (Scorpion) (Centruroides nigrovariatus baergi)

Centruroides bicolor (Scorpion)

Centruroides bonito (Scorpion)

Centruroides elegans (Bark scorpion)

Centruroides exilicauda (Bark scorpion) (Buthus exilicauda)

Centruroides gracilis (Slenderbrown scorpion) (Florida bark scorpion)

Centruroides huichol (Scorpion)

Centruroides infamatus (Kock scorpion)

Centruroides limpidus (Mexican scorpion)

Centruroides margaritatus (Central American bark Scorpion)

Centruroides noxius (Mexican scorpion)

Centruroides ornatus (Scorpion) (Centruroides infamatus ornatus)

Centruroides sculpturatus (Arizona bark scorpion)

Centruroides suffusus (Durango bark scorpion)

Centruroides tecomanus (Scorpion) (Centruroides limpidus tecomanus)

Centruroides vittatus (Striped bark scorpion)

Ceratogyrus darlingi (Rear horned baboon tarantula)

Ceratogyrus marshalli (Straighthorned baboon tarantula) (Ceratogyrus cornuatus)

Chilobrachys guangxiensis (Chinese earth tiger tarantula) (Chilobrachys jingzhao)

Chromatopelma cyaneopubescens (Greenbottle blue tarantula) (Eurypelma cyaneopubescens)

Conasprella delessertii (Sozon's cone) (Conus delessertii)

Condylactis gigantea (Giant Caribbean anemone) (Condylactis passiflora)

Conus achatinus (Little frog cone)

Conus amadis (Amadis cone)

Conus ammiralis (Admiral cone)

Conus ateralbus (Cone snail)

Conus aurisiacus (Aurisiacus cone)

Conus betulinus (Beech cone)

Conus bullatus (Bubble cone)

Conus catus (Cat cone)

Conus consors (Singed cone)

Conus eburneus (Ivory cone)

Conus ermineus (Agate cone) (Chelyconus ermineus)

Conus figulinus (Fig cone)

Conus geographus (Geography cone) (Nubecula geographus)

Conus gloriamaris (Glory-of-the-Sea cone)

Conus kinoshitai (Kinoshita's cone)