Pandinotoxin

Pandinotoxins are toxins from the venom of the emperor scorpion Pandinus imperator. They are selective blockers of voltage-gated potassium channels ^[1]

Pandinotoxin
Schematic diagram of the three-dimensional of Pandinotoxin
Identifiers
Organism	Pandinus imperator
Symbol	N/A

Sources

The source for the pandinotoxins is the venom of the scorpion Pandinus imperator.^[1]

Chemistry

Family

The toxins of the family are designated pandinotoxin (PiTX)-Kα, PiTX-Kβ, and PiTX-Kγ ^[2] They are members of the α-KTx family of scorpion toxins.^[1]

Structure and homology

The sequences of Pandinotoxins
CTX ZFTNVSCTTSKE-CWSVCQRLHNTSR-GKCMNKKCRCYS PiTXK- α ---TISCTNPKQ-CYPHCKKETGYPN-AKCMNRKCKCFGR PiTXK- β ---TISCTNEKQ-CYPHCKKETGYPN-AKCMNRKCKCFGR PiTX-K γ ---LVKCRGTSD-CGRPCQQQTGCPN-SKCINRMCKCYGC Figure 1: Sequence of Pandinotoxins. Adapted from Solution Structure for Pandinus Toxin K-R (PiTX-KR) [1]

Pandinotoxin Kα and -β

The amino acid sequences of PiTX-K α and PiTX-K β are identical, except for the seventh amino acid: a proline in PiTX-Kα and a glutamic acid in PiTX-Kβ ^[2](see Fig.1).

PiTX-Kα and PiTX-Kβ are 35-residue peptides, which are found to have an α-helix from residues 10 to 21 and two β-sheets (β 1 is from residues 26-28, β 2 is from residues 33-35). One face of the α-helix is anchored to the β-sheet by three disulfide bonds which are conserved in all members of the charybdotoxin family (R-K toxins).^[1] PiTX-K α and PiTX-K β have only two β-sheets whereas other members of the family have three additional amino acid residues at the N-terminal portion, which forms a third β-sheet.^[1]

Pandinotoxin Kγ

Pandinotoxin Kγ has not yet been investigated.

Target

Pandinotoxins are the most potent inhibitors of the rapidly inactivating A-type voltage-gated potassium channels.^[3] They also block the delayed rectifier, slowly inactivating channels of the subfamily A member 2 (Kv1.2/KCNA2) [1] and they can reversibly block the shaker B potassium-channels (Kv1.1 sub-family).^[4]

Mode of action

The residue K27, a lysine at place 27 of the protein sequence, interacts with the voltage sensitivity blocking activity of CTX channels. It is conserved among PiTX-K α and PiTX-K β. This amino acid is located nearby the selectivity filter of the pore ^[5] and it is responsible for the interaction with A-type channels by being inserted in the pore of the ion channels.^[1] The structural differences in the backbone and side chain between PiTX-Kα and CTX result in a higher affinity for A-type channels for PiTX-Kα.^[1] The affinity for the Shaker B K⁺ channel is significantly smaller for PiTX-Kβ in comparison with PiTX-Kα owing to the changes in the seventh residue.^[4]

Therapeutic use

Intraplantarly injection of PiTX-Kα before or after the administration of diclofenac produces a significant reduction in spontaneous flinching, mechanical allodynia and thermal hyperalgesia in a rat model for bone cancer. Downregulation of PiTX-Kα almost completely eliminates diclofenac-induced anti-nociception.^[6]