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.