Voltage Gated Ion Channel Function: Gating, Conduction, and the Role of Water and Protons

Abstract

Ion channels, which are found in every biological cell, regulate the concentration of electrolytes, and are responsible for multiple biological functions, including in particular the propagation of nerve impulses. The channels with the latter function are gated (opened) by a voltage signal, which allows Na+ into the cell and K+ out. These channels have several positively charged amino acids on a transmembrane domain of their voltage sensor, and it is generally considered, based primarily on two lines of experimental evidence, that these charges move with respect to the membrane to open the channel. At least three forms of motion, with greatly differing extents and mechanisms of motion, have been proposed. There is a “gating current”, a capacitative current preceding the channel opening, that corresponds to several charges (for one class of channel typically 12–13) crossing the membrane field, which may not require protein physically crossing a large fraction of the membrane. The coupling to the opening of the channel would in these models depend on the motion. The conduction itself is usually assumed to require the “gate” of the channel to be pulled apart to allow ions to enter as a section of the protein partially crosses the membrane, and a selectivity filter at the opposite end of the channel determines the ion which is allowed to pass through. We will here primarily consider K+ channels, although Na+ channels are similar. We propose that the mechanism of gating differs from that which is generally accepted, in that the positively charged residues need not move (there may be some motion, but not as gating current). Instead, protons may constitute the gating current, causing the gate to open; opening consists of only increasing the diameter at the gate from approximately 6 Å to approximately 12 Å. We propose in addition that the gate oscillates rather than simply opens, and the ion experiences a barrier to its motion across the channel that is tuned by the water present within the channel. Our own quantum calculations as well as numerous experiments of others are interpreted in terms of this hypothesis. It is also shown that the evidence that supports the motion of the sensor as the gating current can also be consistent with the hypothesis we present.

Evidence of Polaron Excitations in Low Temperature Raman Spectra of Oxalic Acid Dihydrate

“…Recent advances in study of voltage gated proton channels revealed the intricate mechanism of membrane depolarization which triggers the proton flow from the cell 3 and the role which amino acid vibrations might play in opening and closing of the proton channel 4 .…”

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

“…The cycle is indicated in Fig. 9, reproduced from (40). This implies that the gate can complex K + well enough to force the ion in the cavity to move up, or at least allow it to move up.…”

“…Can the evidence that has been accumulated over the past several decades be interpreted other than by the standard model? We have offered an alternative, proton transport, which would provide the gating current, and would be able to open and close the gate (40)(41)(42)(43)(44)(45), but must show that the evidence that has been interpreted in terms of the standard model can be interpreted without it.…”

“…If the arginines are not charged this does not apply, but then the arginines would not contribute to gating current. (40).…”

Mutational Consequences of Aberrant Ion Channels in Neurological Disorders

“…With the opening of sodium channel, membrane potential shifted from -70 mV to less negative values due to the influx of positive sodium ions thereby elevating the positive charge inside the membrane. Kariev and Green proposed and provided the evidence that protons constitute the gating current to open the channel (Kariev and Green 2012). Based on the genetic diversity, they are classified into different subtypes (i.e., Na v 1.1 to Na v 1.9) that are known to be associated with various diseases summarized in Table 1.…”