Hg1, novel peptide inhibitor specific for Kv1.3 channels from first scorpion Kunitz-type potassium channel toxin family.

Abstract

The potassium channel Kv1.3 is an attractive pharmacological target for autoimmune diseases. Specific peptide inhibitors are key prospects for diagnosing and treating these diseases. Here, we identified the first scorpion Kunitz-type potassium channel toxin family with three groups and seven members. In addition to their function as trypsin inhibitors with dissociation constants of 140 nM for recombinant LmKTT-1a, 160 nM for LmKTT-1b, 124 nM for LmKTT-1c, 136 nM for BmKTT-1, 420 nM for BmKTT-2, 760 nM for BmKTT-3, and 107 nM for Hg1, all seven recombinant scorpion Kunitz-type toxins could block the Kv1.3 channel. Electrophysiological experiments showed that six of seven scorpion toxins inhibited ~50-80% of Kv1.3 channel currents at a concentration of 1 μM. The exception was rBmKTT-3, which had weak activity. The IC(50) values of rBmKTT-1, rBmKTT-2, and rHg1 for Kv1.3 channels were ~129.7, 371.3, and 6.2 nM, respectively. Further pharmacological experiments indicated that rHg1 was a highly selective Kv1.3 channel inhibitor with weak affinity for other potassium channels. Different from classical Kunitz-type potassium channel toxins with N-terminal regions as the channel-interacting interfaces, the channel-interacting interface of Hg1 was in the C-terminal region. In conclusion, these findings describe the first scorpion Kunitz-type potassium channel toxin family, of which a novel inhibitor, Hg1, is specific for Kv1.3 channels. Their structural and functional diversity strongly suggest that Kunitz-type toxins are a new source to screen and design potential peptides for diagnosing and treating Kv1.3-mediated autoimmune diseases.

• Authors: Zong-Yun Chen, You-Tian Hu, Wei-Shan Yang, Ya-Wen He, Jing Feng, Bin Wang, Rui-Ming Zhao, Jiu-Ping Ding, Zhi-Jian Cao, Wen-Xin Li, Ying-Liang Wu
• Journal: The Journal of biological chemistry (J Biol Chem) Vol. 287 Issue 17 Pg. 13813-21 (Apr 20 2012) ISSN: 1083-351X [Electronic] United States
• PMID: 22354971 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Hg1 toxin, Hadrurus gertschi
• Kv1.3 Potassium Channel
• Peptides
• Potassium Channels
• Scorpion Venoms
• Trypsin Inhibitors
• Venoms

Topics

• Amino Acid Sequence
• Animals
• Autoimmune Diseases (metabolism)
• Cattle
• Electrophysiology (methods)
• Gene Library
• HEK293 Cells
• Humans
• Inhibitory Concentration 50
• Kv1.3 Potassium Channel (chemistry)
• Molecular Sequence Data
• Peptides (chemistry)
• Potassium Channels (chemistry)
• Protein Interaction Mapping (methods)
• Scorpion Venoms (chemistry, pharmacology)
• Scorpions
• Sequence Homology, Amino Acid
• Swine
• Trypsin Inhibitors (pharmacology)
• Venoms (metabolism)