Oral Presentation 2014 International Biophysics Congress

Design principles of voltage sensors in ion channels (#204)

Zhe Lu 1
  1. University of Pensylvania/HHMI, Philadelphia, PA, USA

Voltage-gated ion channels underlie rapid electric signaling in excitable cells such as neurons. While intense investigation over a half century has dramatically enhanced our understanding of their voltage-gating mechanism, fundamental questions remain. For example, what type of chemical energy must the electric energy overcome to tilt the channel gating equilibrium? As in other proteins, the conformational states of a given channel’s voltage sensors have their characteristic equilibrium distribution, i.e., are governed by an intrinsic chemical equilibrium. That distribution cannot be strongly biased in one or the other direction if nature is to exploit modest physiological changes in membrane potential to tilt the voltage sensor toward open or closed states. That is, given a modest free energy difference between open and closed states, a channel’s open probability can usefully range from high to near zero. The question of how the requisite delicately balanced chemical equilibrium of a voltage sensor is achieved has been poorly understood. Additionally, electrophysiological studies have established that the N-terminal half of the fourth transmembrane segment (NTS4) of these channels functions as the primary voltage sensor. However, the highly anticipated crystal structures of voltage-gated ion channels have revealed that, contrary to expectation, NTS4 is not located within a proteinaceous pore. Rather, it and the C-terminal half of S3 (CTS3) form a helix-turn-helix motif, termed the voltage-sensor paddle. This unexpected structural finding raises two fundamental questions: does the paddle motif also exist in voltage-gated channels in a biological membrane and, if so, what is its function in voltage gating? Our studies on voltage-gated Shaker K+ channels show that the paddle motif exists in the open state of these channels operating in a biological membrane, and that CTS3 acts as an extracellular hydrophobic "stabilizer" for NTS4, biasing the gating chemical equilibrium towards the open state.