Potassium channel Xavier

      Potassium Channels control cell membrane electric potentials by selectively allowing diffusion of K⁺ across the membrane.^[1] K⁺

The structure is comprised of 4 identical subunits. Each subunit has a voltage sensor and one fourth of the pore. There is the transmembrane region marked between the parallel lines in the figure. This region houses the channel pore, composed of interwoven helices in a teepee conformation, the all-important “selectivity filter”, providing the channel with its remarkable 10,00 fold selectivity for K⁺ ions over Na⁺ ions and the “voltage sensor” which is uses well placed arginine and acidic residues to determine the membrane polarity and open/close the channel in response.^[2]

See what the The open channel looks like vs. The closed channel (1k4c). Or view the morph of the channel opening and closing (Cartoon Design).

Contents 1 Overall mechanism 2 Entering the hydrophobic pocket 3 Aqueous cavity and desolvation 4 Selectivity Filter and Pore 4.1 Why K+ and not Na+ 4.2 Knock-on mechanism 5 Physical gating: The Voltage Sensor Domain (VSD) 5.1 Hydrophobic gating: Dewetting

Overall mechanism

The main steps that potassium ions go trough when leaving the cell are:

• Entering the hydrophobic pocket
• Aqueous cavity and desolvation
• Selectivity filter
• Explaining the voltage sensor and closing/opening of channel

Entering the hydrophobic pocket

It is important to notice that with the exception of the selectivity filter, the pore lining is mainly hydrophobic. The entrance of the channel, at the bottom of the 34Å pore containing transmembrane region lies a number of aromatic residues which help form a seal between the pore and the intracellular cytoplasm. This domain is called the lower gate.

Aqueous cavity and desolvation

This hydrophobic lining provides an inert surface over which the diffusing ion can slide unimpaired, without getting attached anywhere until the aqueous cavity. At the end of the hydrophobic porus there is an aqueous cavity (Spinning Model). At this point, K⁺ ions find a position of hydration and get ready to be dehydrated and get into the selectivity filter.

Selectivity Filter and Pore

At this point it is clear to see where the channels remarkable selectivity comes from. When entering the selectivity filter, K⁺ ions are first dehydrated, shedding up to 8 waters of the aqueous cavity.

Another factor that drives the cations leave the aqueous cavity and enter the selectivity filter is the natural polarity of the helices, with the carbonyl oxygens pointing at the entrance of the selectivity filter

Why K+ and not Na+

To stabilize these naked ions, a number of carbonyl oxygens (Labels) bind the K⁺ ions. The distance between K⁺ ion and carbonyl oxygen is at the perfect width to accommodate K⁺ ions but not Na⁺, ions which are too small. If a Na⁺ ion were to lose its water shell, the carbonyl oxygens could not successfully stabilize it in its naked form and thus it is energetically unfavorable for a Na⁺ ion to enter the channel.

Knock-on mechanism

There is room within the selectivity filter for four potassium ions. This, as it turns out, is crucial as the presence of the positive cations in close proximity to one another effectively pushes the potassium ions through the filter via electrostatic forces (the knock-on mechanism). This helps explain how the potassium channel can have such a rapid turnover rate. Compared to the high-concentration channel (1k4c), when exposed to a low concentration of potassium, the channel assumes a "low concentration" conformation (1k4d) which is sealed shut via interactions with water molecules.^[1]

Physical gating: The Voltage Sensor Domain (VSD)

Channel pore opening is dependent on the membrane voltage, a characteristic that is “sensed” by the voltage sensor. The voltage sensor is comprised of six helices, S0, S1, S2, S3, S4, & S5. Negatively charged sensor residues are either located in the external cluster, consisting of Glu 183 (in the 2r9r structure) and Glu 226, or in the internal cluster consisting of Glu 154, Glu 236, and Asp 259. The external cluster is exposed to solvent while the internal cluster is buried. Phenylalanine 233 acts as a separator between the two clusters.^[2] The 7 positively charged residues of the voltage sensor are located on the S4 helix. Lys 302 and Arg 305 form hydrogen bonds with the internal negative cluster while Arginines 287, 290, 293, 296 and 299 are exposed to the extracellular solution (Overview). When the voltage sensor is exposed to a strong negative electric field in the intracellular membrane, the positive gating charges shift inward with the α-carbon of Arg 290 coming in close proximity to Phe 233. This shift effectively squeezes the pore shut, closing the intracellular-extracellular pathway. For a comparison see: The Open Channel vs. The Closed (1k4c) Channel.^[2] Or view the morph of the channel opening and closing (Cartoon Design).

Hydrophobic gating: Dewetting

After the channel is physically closed, there is a short period time during which there is still current (ions being pumped). It is not until the waters leave the hydrophobic pocket that ions cannot be stabilized in the hydrophobic part of the pore and therefore not being brought to the selectivity filter. This is called hydrophobic gating, meaning that the gating process is not necessarily mechanical but also chemical.