A high affinity blocker for inward-rectifier K+ channels-Tertiapin-Q

Introduction 

Tertiapin-Q (TPN-Q) is a small compact protein that contains twenty-one amino acids, which derived from bee venom toxin tertiapin (TPN), and it is obtained by replacing methionine residue of TPN with glutamine residue. TPN-Q can highly inhibit the G protein-coupled inwardly rectifying potassium (GIRK1/4) and renal outer medullary potassium channel (ROMK1), which is similar to the functions of TPN in both affinity and specificity. But unlike the TPN whose methionine residue 13 can be oxidized by air and the oxidation hinders its binding to the targeted channels, TPN-Q is a non- air-oxidizable derivative.

Biological Activity

Like TPN, Tertiapin-Q (TPN-Q) also inhibits GIRK1/4 and ROMK1 with nanomolar affinity and does not inhibit the IRK1 channel. The interaction between the ROMK1 channel and TPNQ is a bimolecular reaction, and the stoichiometry between them is one-to-one. TPN-Q consists of an α helix formed by the C-terminal half of the peptide and some extended structures formed by the N-terminal half. The researches indicate that the mutations in the C-terminal α-helix not the N-terminal extended structures dramatically affect TPN-Q-ROMK1 interaction, and many noncysteine residues in the α helix critical for the ROMK1-TPN-Q interaction are not conserved in apamin and mast cell degranulating peptide.

Function

K⁺ channels are the most widely distributed ion channel types in living organisms. They are associated with many physiological functions and can also be involved in the regulation of disease-related processes. In vitro assay, TPN-Q can selective block of GIRK1/4 heterodimer and ROMK1 (Kir), and Kirs are highly K⁺-selective ion channels that carry K⁺ from the extracellular to the intracellular compartment more efficiently than the opposite direction. In vivo assay, TPN-Q is a blocker of muscarinic acetylcholine receptor-operated K⁺ current. After the cessation of rapid atrial pacing, the atrial effective refractory period (AERP) is unchanged during the experimental period in the rapid atrial pacing (RAP) rabbits. K⁺ channels are widely distributed in living organisms, so it is important to identifying specific modulators of these ion channels. TPN-Q can be a very useful molecular probe for exploring the physiological functions and molecular mechanisms of inward-rectifier K⁺ channels.

References:

1. Jin, W., Klem, A. M., Lewis, J. H., & Lu, Z. (1999). Mechanisms of inward-rectifier K+ channel inhibition by tertiapin-Q. Biochemistry, 38(43), 14294-14301.

2. Kanjhan, R., Coulson, E. J., Adams, D. J., & Bellingham, M. C. (2005). Tertiapin-Q blocks recombinant and native large conductance K+ channels in a use-dependent manner. Journal of Pharmacology and Experimental Therapeutics, 314(3), 1353-1361.