A Gating Modulator Peptide Toxin for Shaker-Type KV1 Channels Derived from the Sea Anemone Bunodosoma cangicum

Abstract

Natural peptide toxins are a rich source of channel modulators that act on the extracellular face of Kv channels, either at the external pore mouth or at the voltage-sensing domain (S3-S4 linker). As such, natural toxins provide us with highly selective and potent molecular probes to unravel the structure and function of Kv channels. Toxins binding to the external pore mouth partly or completely block the K+ permeation while those binding to the VSD inhibit channel function by modifying channel gating. The Shaker-related Kv1 channels are targeted by several peptide toxins that block the outer pore mouth but no gating modifiers that shift the voltage-dependence of channel opening have yet been identified. Furthermore, the Kv1.5 channel - an important target for the treatment of atrial fibrillation - has no known external peptide pore blockers, presumably due to the presence of a positively charged arginine residue in the outer pore mouth (R379, equivalent to Shaker T449). Bcg31.16 is a recently discovered peptide neurotoxin derived from the sea anemone Bunodosoma cangicum that inhibited several Kv1 subunits with nM potency. Bcg31.16 caused a concentration-dependent depolarizing shift in the voltage-dependence of channel opening; with 300 nM the shifts amounted to +35 mV and +12 mV for Kv1.3 and Kv1.5, respectively. The voltage-dependence of C-type inactivation displayed similar shifts, as well as the voltage-dependence of the gating kinetics. No significant effect on Kv2.1 was obtained at 1 microMolar. Thus, Bcg31.16 is a new gating modifier toxin of the Kv1 family and a novel peptide toxin to inhibit the Kv1.5 channel. (Support: FWO-G043312N to DJS and JT).