Voltage-Sensor Pharmacology in T-Type Calcium Channels

Abstract

The four voltage sensors in T-type calcium channels have distinct amino acid sequences, raising fundamental questions about their relative contributions to the function and regulation of the channel. Studies of Kv channels identified a S3b-S4 helix-turn-helix motif, termed paddle motif, which moves at the protein-lipid interface to drive activation of the voltage-sensors. This motif is an important pharmacological target for amphipathic neurotoxins and it has been suggested that is conserved in other voltage-gated ion channels. Here we show that the four S3b-S4 paddle motifs within the T-type calcium channel could be transplanted into four-fold symmetric Kv channel to individually examine their contributions to the kinetics of voltage sensor activation and pharmacology.