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.
Highlights
Ion channels are ubiquitous in biological cells
We will look at the function as well as the structure of the channels, and will consider the unorthodox possibility that the gating current may be created by the motion of protons through the voltage sensing domain (VSD)
Just as there is no question that access to cysteine mutants in the arginine positions is state dependent, there is no question that proton transport along the VSD from one side of the membrane to the other is possible
Summary
Ion channels are ubiquitous in biological cells. In bacteria, they regulate the concentration of Na+, K+, and some other ions. We will look at the function as well as the structure of the channels, and will consider the unorthodox possibility that the gating current may be created by the motion of protons through the voltage sensing domain (VSD). The conventional models produce this motion by having the S4-S5 linker pull back about this distance, or, in some versions, much more It is this conventional view that we wish to compare to the consequences of proton motion on the gating section of the channel, and related differences in the way the channel functions. 2. Conventional Models “Conventional models”, as just defined, are those that derive the gating current of voltage gated channels from the physical motion of the S4 TM segment of the VSD. The basic experiments in these classes were done relatively early, and were reviewed by Bezanilla [15] The three classes of conventional models are not compatible with each other, when considered in detail
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