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

Conotoxin A superfamily

Conotoxin I1 superfamily

Conotoxin M family

Conotoxin M superfamily

Conotoxin M superfamily, Conopeptide Y family

Conotoxin O1 superfamily

Conotoxin T superfamily

Long (3 C-C) scorpion toxin superfamily

Long (3 C-C) scorpion toxin superfamily, Sodium channel inhibitor family

Long (3 C-C) scorpion toxin superfamily, Sodium channel inhibitor family, Beta subfamily

Long (4 C-C) scorpion toxin superfamily

Long (4 C-C) scorpion toxin superfamily, Sodium channel inhibitor family

Long (4 C-C) scorpion toxin superfamily, Sodium channel inhibitor family, Alpha subfamily

Long (4 C-C) scorpion toxin superfamily, Sodium channel inhibitor family, Beta subfamily

Neurotoxin 01 (U2-agtx) family

Neurotoxin 02 (plectoxin) family, 01 (Tx3) subfamily

Neurotoxin 02 (plectoxin) family, 02 (plectoxin) subfamily

Neurotoxin 02 (plectoxin) family, 04 (U16-lycotoxin) subfamily

Neurotoxin 03 (Tx2) family, 04 subfamily

Neurotoxin 03 (Tx2) family, 05 subfamily

Neurotoxin 03 (Tx2) family, 06 subfamily

Neurotoxin 04 (omega-agtx) family, 02 (Tx1) subfamily

Neurotoxin 06 (delta-actx) family

Neurotoxin 07 (Beta/delta-agtx) family

Neurotoxin 07 (Beta/delta-agtx) family, 01 (aga-2) subfamily

Neurotoxin 07 (Beta/delta-agtx) family, 02 (aga-3) subfamily

Neurotoxin 07 (Beta/delta-agtx) family, 03 (aga-4) subfamily, Aga sub-subfamily

Neurotoxin 07 (Beta/delta-agtx) family, 04 (aga-5) subfamily

Neurotoxin 08 (Shiva) family, 01 (omega toxin) subfamily

Neurotoxin 10 (Hwtx-1) family

Neurotoxin 10 (Hwtx-1) family, 04 (CcoTx1) subfamily

Neurotoxin 10 (Hwtx-1) family, 07 (GrTx) subfamily

Neurotoxin 10 (Hwtx-1) family, 08 (Gtx1-15) subfamily

Neurotoxin 10 (Hwtx-1) family, 09 (HaTx) subfamily

Neurotoxin 10 (Hwtx-1) family, 10 (haplotoxin-1) subfamily

Neurotoxin 10 (Hwtx-1) family, 11 (haplotoxin-2) subfamily

Neurotoxin 10 (Hwtx-1) family, 14 (Hntx-1) subfamily

Neurotoxin 10 (Hwtx-1) family, 15 (Hntx-3) subfamily

Neurotoxin 10 (Hwtx-1) family, 18 (Hntx-VII) subfamily

Neurotoxin 10 (Hwtx-1) family, 22 (Htx-4) subfamily

Neurotoxin 10 (Hwtx-1) family, 23 (HwTx-I) subfamily

Neurotoxin 10 (Hwtx-1) family, 28 (Jztx-11) subfamily

Neurotoxin 10 (Hwtx-1) family, 33 (Jztx-1) subfamily

Neurotoxin 10 (Hwtx-1) family, 34 (Jztx-26) subfamily

Neurotoxin 10 (Hwtx-1) family, 36 (Jztx-2) subfamily

Neurotoxin 10 (Hwtx-1) family, 37 (Jztx-31) subfamily

Neurotoxin 10 (Hwtx-1) family, 39 (Jztx-34) subfamily

Neurotoxin 10 (Hwtx-1) family, 44 (Jztx-4) subfamily

Neurotoxin 10 (Hwtx-1) family, 47 subfamily

Neurotoxin 10 (Hwtx-1) family, 51 (Hntx-8) subfamily

Neurotoxin 10 (Hwtx-1) family, 51 (Hntx-8) subfamily, Hntx-8 sub-subfamily

Neurotoxin 10 (Hwtx-1) family, 52 (MTx4) subfamily

Neurotoxin 10 (Hwtx-1) family, 54 (ProTx-1) subfamily

Neurotoxin 10 (Hwtx-1) family, 55 (ProTx-III) subfamily

Neurotoxin 10 (Hwtx-1) family, 56 (SNX-482) subfamily

Neurotoxin 10 (Hwtx-1) family, 59 (Tltx) subfamily

Neurotoxin 10 (Hwtx-1) family, 60 (Tx2-9) subfamily

Neurotoxin 10 (Hwtx-1) family, 61 (VSTX3) subfamily

Neurotoxin 10 (Hwtx-1) family, 62 (Vatx) subfamily

Neurotoxin 10 (Hwtx-1) family, 63 (VsTx1) subfamily

Neurotoxin 12 (Hwtx-2) family, 01 (Ap1a) subfamily

Neurotoxin 13 (insecticidal toxin ABC) family, 01 (Aps III) subfamily

Neurotoxin 14 (magi-1) family, 01 (HNTX-16) subfamily

Neurotoxin 14 (magi-1) family, 08 (Ltx-4) subfamily

Neurotoxin 14 (magi-1) family, 09 (magi-1) subfamily

Neurotoxin 15 family, 01 (magi-5) subfamily

Neurotoxin 16 (SFI) family

Neurotoxin 19 (CSTX) family

Neurotoxin 26 (DTX) family

Neurotoxin 28 (Litx) family

Neurotoxin 30 (phrixotoxin) family

Neurotoxin 39 family

Non-disulfide-bridged peptide (NDBP) superfamily

Non-disulfide-bridged peptide (NDBP) superfamily, Short antimicrobial peptide (group 4) family

Not in a family

Phospholipase A2 family, Group II subfamily, Q49 sub-subfamily

Phrixotoxin family

RTX family