A bifunctional sea anemone peptide with Kunitz type protease and potassium channel inhibiting properties.

Steve Peigneur (1) , Bert Billen (1) , Rita Derua (2) , Etienne Waelkens (2) , Sarah Debaveye (1) , László Béress , Jan Tytgat (1)

1 KU Leuven - Catholic University of Leuven = Katholieke Universiteit Leuven
2 University of leuven

Sea anemone venom is a known source of interesting bioactive compounds, including peptide toxins which are invaluable tools for studying structure and function of voltage-gated potassium channels. APEKTx1 is a novel peptide isolated from the sea anemone , containing 63 amino acids cross-linked by 3 disulfide bridges. Sequence alignment reveals that APEKTx1 is a new member of the type 2 sea anemone peptides targeting voltage-gated potassium channels (K's), which also include the kalicludines from . Similar to the kalicludines, APEKTx1 shares structural homology with both the basic pancreatic trypsin inhibitor (BPTI), a very potent Kunitz-type protease inhibitor, and dendrotoxins which are powerful blockers of voltage-gated potassium channels. In this study, APEKTx1 has been subjected to a screening on a wide range of 23 ion channels expressed in oocytes: 13 cloned voltage-gated potassium channels (K1.1-K1.6, K1.1 triple mutant, K2.1, K3.1, K4.2, K4.3, hERG, the insect channel IR), 2 cloned hyperpolarization-activated cyclic nucleotide-sensitive cation non-selective channels (HCN1 and HCN2) and 8 cloned voltage-gated sodium channels (Na1.2-Na1.8 and the insect channel DmNa1). Our data shows that APEKTx1 selectively blocks K1.1 channels in a very potent manner with an IC value of 0.9nM. Furthermore, we compared the trypsin inhibitory activity of this toxin with BPTI. APEKTx1 inhibits trypsin with a dissociation constant of 124nM. In conclusion, this study demonstrates that APEKTx1 has the unique feature to combine the dual functionality of a potent and selective blocker of K1.1 channels with that of a competitive inhibitor of trypsin.

Mots clés: K channel inhibitor; sea anemone toxin; protease inhibitor

Domaines: Pharmacologie

Steve Peigneur, Bert Billen, Rita Derua, Etienne Waelkens, Sarah Debaveye, et al.. A bifunctional sea anemone peptide with Kunitz type protease and potassium channel inhibiting properties.. Biochemical Pharmacology, 2011, 82 (1), pp.81. ⟨10.1016/j.bcp.2011.03.023⟩. ⟨hal-00701259⟩