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8.B.5 The Na+/K+/Ca2+ Channel Targeting Tarantula Huwentoxin (THT) Family

Protoxins inhibit voltage-gated calcium (Cav3.1/CACNA1G), potassium (Kv2.1/KCNB1) and sodium (Nav1.5) channels and shift the voltage-dependence of channel activation to more positive potentials. They potently inhibit all sodium channel subtypes tested (Nav1.2/SCN2A, Nav1.5/SCN5A, Nav1.7/SCN9A, and Nav1.8/SCN10A).

Protoxins 1 (35aas) and 2 (30aas) are peptide toxins from the venom of the tarantula, Thrixopelma pruriens, that conform to the inhibitory cystine knot motif and which modify activation kinetics of Nav and Cav, but not Kv, channels. ProTx-II inhibits current by shifting the voltage dependence of activation to more depolarized potentials (Smith et al., 2007).

Many plant and animal toxins cause aversive behaviors in animals due to their pungent or unpleasant taste or because they cause other unpleasant senstations like pain. Cromer and McIntyre (2007) have reviewed toxins that act at the TRPV1 ion channel expressed in primary sensory neurons. This channel is activated by multiple painful stimuli and is thought to be a key pain sensor and integrator. The painful peptide 'vanillotoxin' components of tarantula toxin activate the TRPV1 ion channel to cause pain. Toxins from plants, spiders and jellyfish that act on TRPV1 have been identified. Structural information about sites of interaction (toxin-binding sites on the Kv ion channel) have been evaluated. Toxin agonists such as resiniferatoxin and vanillotoxins were proposed to interact with a region of TRPV1 that is homologous to the 'voltage sensor' in the Kv1.2 ion channel, to open the channel and activate primary sensory nerves, causing pain (Cromer and McIntyre, 2007).

The voltage-sensor paddle is a crucial structural motif in voltage-activated potassium (K(v)) channels that has been proposed to move at the protein-lipid interface in response to changes in membrane voltage. Tarantula toxins like hanatoxin and SGTx1 inhibit K(v) channels by interacting with paddle motifs within the membrane (Milescu et al., 2007). These toxins can partition into membranes under physiologically relevant conditions, but the toxin-membrane interaction is not sufficient to inhibit K(v) channels. These require specific binding to the paddle motif.

This family belongs to the: Conotoxin Superfamily.

References associated with 8.B.5 family:

Cromer, B.A., and P. McIntyre. (2008). Painful toxins acting at TRPV1. Toxicon. 51: 163-73. 18061640
Diao, J., Y. Lin, J. Tang, and S. Liang. (2003). cDNA sequence analysis of seven peptide toxins from the spider Selenocosmia huwena. Toxicon. 42: 715-723. 14757201
Escoubas, P., S. Diochot, M.L. Célérier, T. Nakajima, and M. Lazdunski. (2002). Novel tarantula toxins for subtypes of voltage-dependent potassium channels in the Kv2 and Kv4 subfamilies. Mol. Pharmacol. 62: 48-57. 12065754
Henriques, S.T., E. Deplazes, N. Lawrence, O. Cheneval, S. Chaousis, M. Inserra, P. Thongyoo, G.F. King, A.E. Mark, I. Vetter, D.J. Craik, and C.I. Schroeder. (2016). Interaction of Tarantula Venom Peptide ProTx-II with Lipid Membranes is a Prerequisite for its Inhibition of Human Voltage-gated Sodium Channel NaV1.7. J. Biol. Chem. [Epub: Ahead of Print] 27311819
Lau, C.H., G.F. King, and M. Mobli. (2016). Molecular basis of the interaction between gating modifier spider toxins and the voltage sensor of voltage-gated ion channels. Sci Rep 6: 34333. 27677715
Liao, Z., C. Yuan, M. Deng, J. Li, J. Chen, Y. Yang, W. Hu, and S. Liang. (2006). Solution structure and functional characterization of jingzhaotoxin-XI: a novel gating modifier of both potassium and sodium channels. Biochemistry. 45: 15591-15600. 17176080
Middleton, R.E., V.A. Warren, R.L. Kraus, J.C. Hwang, C.J. Liu, G. Dai, R.M. Brochu, M.G. Kohler, Y.D. Gao, V.M. Garsky, M.J. Bogusky, J.T. Mehl, C.J. Cohen, and M.M. Smith. (2002). Two tarantula peptides inhibit activation of multiple sodium channels. Biochemistry 41: 14734-14747. 12475222
Milescu, M., J. Vobecky, S.H. Roh, S.H. Kim, H.J. Jung, J.I. Kim, and K.J. Swartz. (2007). Tarantula toxins interact with voltage sensors within lipid membranes. J. Gen. Physiol. 130: 497-511. 17938232
Ono, S., T. Kimura, and T. Kubo. (2011). Characterization of voltage-dependent calcium channel blocking peptides from the venom of the tarantula Grammostola rosea. Toxicon 58: 265-276. 21740921
Ozawa, S., T. Kimura, T. Nozaki, H. Harada, I. Shimada, and M. Osawa. (2015). Structural basis for the inhibition of voltage-dependent K+ channel by gating modifier toxin. Sci Rep 5: 14226. 26382304
Priest, B.T., K.M. Blumenthal, J.J. Smith, V.A. Warren, and M.M. Smith. (2007). ProTx-I and ProTx-II: gating modifiers of voltage-gated sodium channels. Toxicon 49: 194-201. 17087985
Ramracheya, R., C. Ward, M. Shigeto, J.N. Walker, S. Amisten, Q. Zhang, P.R. Johnson, P. Rorsman, and M. Braun. (2010). Membrane potential-dependent inactivation of voltage-gated ion channels in α-cells inhibits glucagon secretion from human islets. Diabetes 59: 2198-2208. 20547976
Smith, J.J., T.R. Cummins, S. Alphy, K.M. Blumenthal. (2007). Molecular interactions of the gating modifier toxin ProTx-II with Nav 1.5. J. Biol. Chem. 282.17; 12687-12697. 17339321
Takahashi, H., J.I. Kim, H.J. Min, K. Sato, K.J. Swartz, and I. Shimada. (2000). Solution structure of hanatoxin1, a gating modifier of voltage-dependent K+ channels: common surface features of gating modifier toxins. J. Mol. Biol. 297: 771-780. 10731427
Zhang, P.F., P. Chen, W.J. Hu, and S.P. Liang. (2003). Huwentoxin-V, a novel insecticidal peptide toxin from the spider Selenocosmia huwena, and a natural mutant of the toxin: indicates the key amino acid residues related to the biological activity. Toxicon. 42: 15-20. 12893056