Precious Natural Peptides from Spider Venoms: New Tools for Studying Potassium Channels

Abstract

Among the large variety of animal toxins that target potassium channels, spider peptides constitute an unique class of voltage-dependent K+ (Kv) current inhibitors according to their structure and pharmacological properties. Spider toxins that block Kv currents are small basic peptides the include three disuflide bridges and belong to the family of inhibitor cystine knot (ICK) molecules. Unlike snake, bee, scorpion, or sea anemone toxins that block Kv1 or Kv3 channels, ICK spider toxins target Kv2 and Kv4 channels, which are expressed in the central nervous system (CNS) and in the cardiovascular system. Their selective affinities for Kv2 and/or Kv4 subfamilies are very useful for dissecting these currents in neuronal and cardiac cells and for the determination of their contribution in physiological processes. Their mode of action is also original, since they induce a shift of channel opening to more depolarized potentials that alter the voltage-dependent properties of K currents. Then they are called gating modifiers. Structure-function studies of these gating modifiers were recently facilitated by solving their tridimensional structure together with the crystallization of prokaryotic K+ channels. Spider toxins present an active molecular surface, including a hydrophobic patch surrounded by charged residues, which are important for their binding on Kv channels. Gating modifiers interact with important residues in the S3C-S4 external loop via both hydrophobic and electrostatic interactions. Several dynamic interaction models were proposed, but all of them remain putative.