A Resonance Model gives the Response to Membrane Potential for an Ion Channel: II. Simplification of the Calculation, and Prediction of Stochastic Resonance

Fatade, Ayowumi; Snowhite, Jerry; Green, Michael E.

doi:10.1006/jtbi.2000.2137

Cited by 9 publications

(12 citation statements)

References 12 publications

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“…These are consistent with a threshold in gating, which would be appropriate for the “piquito”. It has been shown that the threshold can produce essentially the same sigmoidal gating current-potential curve as the standard Boltzmann assumption, as well as the non-linearities that are observed [45,46]. This also comes with a prediction of stochastic resonance, but on this there is no pertinent literature, as far as we are aware.…”

Section: Evidence Supporting the New Parts Of The Modelmentioning

confidence: 95%

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

Kariev

Green

2012

IJMS

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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.

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Section: Evidence Supporting the New Parts Of The Modelmentioning

confidence: 95%

“…The fluctuations of the initial motion would be a consequence of a threshold of matching energy levels. There would be a sigmoidal distribution of open probability, which could be indistinguishable from the Boltzmann model [45,46]. …”

Section: Evidence Supporting the New Parts Of The Modelmentioning

confidence: 99%

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

Kariev

Green

2012

IJMS

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“…However, Green and coworkers (81,82) found that this could be explained if there is a threshold for the first transition leading to the start of gating current; the standard model seems to rule out thresholds because the current-voltage gating current curve fits a Boltzmann curve for a single transition (as previously noted, this is an oversimplification (21): see eqn. 1).…”

Section: )mentioning

confidence: 98%

“…1). However, if the threshold is distributed as an nearly Gaussian curve of width approximately k B T, then one gets a very similar curve (83). This said, the piquito, with threshold, does not rule out the standard models, if the rise time is not too much faster than 1 µs.…”

Section: )mentioning

confidence: 99%

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

Kariev

Green

2018

Preprint

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Over two-thirds of a century ago, Hodgkin and Huxley proposed the existence of voltage gated ion channels (VGIC) 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 VGIC was determined in the open (ion conducting) state. This type of channel consists of four voltage sensing domains (VSD), 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 K v 1.2 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.

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“…Proton tunneling has been previously discussed in this context. 37,39,40 (E) Proton tunneling would be a first step in transferring protons along the water wire that appears to exist neighboring the S4 TM segment. Even prior to calculations, we should expect such a water wire, as there is clearly space for it, and given the results on access to S4, essential certainty that water must be able to reach this volume.…”

Section: How the Model Functionsmentioning

confidence: 99%

Consequences of phosphate-arginine complexes in voltage gated ion channels

Green¹

2008

Channels

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There are two reasons for suspecting that phosphate complexes of arginine make it very difficult to derive gating charge in voltage gated potassium (and presumably sodium) channels from the motion of charged arginines. For one thing, the arginines should be complexed with phosphate, thereby neutralizing the charge, at least partially. Second, Li et al. 1 have shown that there is a large energy penalty for putting a charged arginine into a membrane. Ion channel gating current is generally attributed to S4 motion, in that the S4 segment of the voltage sensing domain (VSD) of these channels contains arginines, some of which are not (or at least not obviously) salt bridged, or otherwise charge compensated. There is, however, good reason to expect that there should be a complex of these arginines with phosphate, very probably from lipid headgroups. This has consequences for gating current; the complexed arginines, if they moved, would carry too much of the membrane along. This leads to the suggestion that an alternative to S4 physical motion, H + transport, should be considered as a possible resolution of the apparent paradox. The consequences for a gating model that was proposed in our earlier work are discussed; there is one major difference in the model in the present form (a conformational change), but the proton cascade as gating current and the role of water in the closed state are reinforced.

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A Resonance Model gives the Response to Membrane Potential for an Ion Channel: II. Simplification of the Calculation, and Prediction of Stochastic Resonance

Cited by 9 publications

References 12 publications

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

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

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

Consequences of phosphate-arginine complexes in voltage gated ion channels

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