The Role of Proton Transport in Gating Current in a Voltage Gated Ion Channel, as Shown by Quantum Calculations.

Over two-thirds of a century ago, Hodgkin and Huxley proposed the existence of voltage gated ion channels (VGICs) to carry Na⁺ and K⁺ ions across the cell membrane to create the nerve impulse, in response to depolarization of the membrane. The channels have multiple physiological roles, and play a central role in a wide variety of diseases when they malfunction. The first channel structure was found by MacKinnon and coworkers in 1998. Subsequently, the structure of a number of VGICs was determined in the open (ion conducting) state. This type of channel consists of four voltage sensing domains (VSDs), each formed from four transmembrane (TM) segments, plus a pore domain through which ions move. Understanding the gating mechanism (how the channel opens and closes) requires structures. One TM segment (S4) has an arginine in every third position, with one such segment per domain. It is usually assumed that these arginines are all ionized, and in the resting state are held toward the intracellular side of the membrane by voltage across the membrane. They are assumed to move outward (extracellular direction) when released by depolarization of this voltage, producing a capacitive gating current and opening the channel. We suggest alternate interpretations of the evidence that led to these models. Measured gating current is the total charge displacement of all atoms in the VSD; we propose that the prime, but not sole, contributor is proton motion, not displacement of the charges on the arginines of S4. It is known that the VSD can conduct protons. Quantum calculations on the Kv1.2 potassium channel VSD show how; the key is the amphoteric nature of the arginine side chain, which allows it to transfer a proton. This appears to be the first time the arginine side chain has had its amphoteric character considered. We have calculated one such proton transfer in detail: this proton starts from a tyrosine that can ionize, transferring to the NE of the third arginine on S4; that arginine's NH then transfers a proton to a glutamate. The backbone remains static. A mutation predicted to affect the proton transfer has been qualitatively confirmed experimentally, from the change in the gating current-voltage curve. The total charge displacement in going from a normal closed potential of -70 mV across the membrane to 0 mV (open), is calculated to be approximately consistent with measured values, although the error limits on the calculation require caution in interpretation.