Voltage-gated potassium channel

Voltage-gated potassium channels are transmembrane channels specific for potassium and sensitive to voltage changes in the cell's membrane potential. During action potentials, they play a crucial role in returning the depolarized cell to a resting state.

Alpha subunits
Alpha subunits form the actual conductance pore. Based on sequence homology of the hydrophobic transmembrane cores, the alpha subunits of voltage-gated potassium channels are grouped into 12 classes, labeled Kvα1-12. The following is a list of the 40 known human voltage-gated potassium channel alpha subunits grouped first according to function and then subgrouped according to the Kv sequence homology classification scheme:

Delayed rectifier
slowly inactivating or non-inactivating
 * Kvα1.x - Shaker-related: Kv1.1 (KCNA1), Kv1.2 (KCNA2), Kv1.3 (KCNA3), Kv1.5 (KCNA5), Kv1.6 (KCNA6), Kv1.7 (KCNA7), Kv1.8 (KCNA10)
 * Kvα2.x - Shab-related: Kv2.1 (KCNB1), Kv2.2 (KCNB2)
 * Kvα3.x - Shaw-related: Kv3.1 (KCNC1), Kv3.2 (KCNC2)
 * Kvα7.x: Kv7.1 (KCNQ1) - KvLQT1, Kv7.2 (KCNQ2), Kv7.3 (KCNQ3), Kv7.4 (KCNQ4), Kv7.5 (KCNQ5)
 * Kvα10.x: Kv10.1 (KCNH1)

A-type potassium channel
rapidly inactivating
 * Kvα1.x - Shaker-related: Kv1.4 (KCNA4)
 * Kvα3.x - Shaw-related: Kv3.3 (KCNC3), Kv3.4 (KCNC4)
 * Kvα4.x - Shal-related: Kv4.1 (KCND1), Kv4.2 (KCND2), Kv4.3 (KCND3)

Outward-rectifying

 * Kvα10.x: Kv10.2 (KCNH5)

Inward-rectifying
Passes current more easily into the inwards direction (Into the cell).


 * Kvα11.x - ether-a-go-go potassium channels: Kv11.1 (KCNH2) - hERG, Kv11.2 (KCNH6), Kv11.3 (KCNH7)

Slowly activating

 * Kvα12.x: Kv12.1 (KCNH8), Kv12.2 (KCNH3), Kv12.3 (KCNH4)

Modifier/silencer
Unable to form functional channels as homotetramers but instead heterotetramerize with Kvα2 family members to form conductive channels.
 * Kvα5.x: Kv5.1 (KCNF1)
 * Kvα6.x: Kv6.1 (KCNG1), Kv6.2 (KCNG2), Kv6.3 (KCNG3), Kv6.4 (KCNG4)
 * Kvα8.x: Kv8.1 (KCNV1), Kv8.2 (KCNV2)
 * Kvα9.x: Kv9.1 (KCNS1), Kv9.2 (KCNS2), Kv9.3 (KCNS3)

Beta subunits
Beta subunits are auxiliary proteins which associate with alpha subunits, sometimes in a α4β4 stoichiometry. These subunits do not conduct current on their own but rather modulate the activity of Kv channels.
 * Kvβ1 (KCNAB1)
 * Kvβ2 (KCNAB2)
 * Kvβ3 (KCNAB3)
 * minK (KCNE1)
 * MiRP1 (KCNE2)
 * MiRP2 (KCNE3)
 * MiRP3 (KCNE4)
 * KCNE1-like (KCNE1L)
 * KCNIP1 (KCNIP1)
 * KCNIP2 (KCNIP2)
 * KCNIP3 (KCNIP3)
 * KCNIP4 (KCNIP4)

Proteins minK and MiRP1 are putative hERG beta subunits.

Animal research
The voltage-gated K+ channels that provide the outward currents of action potentials have similarities to bacterial K+ channels.

These channels have been studied by X-ray diffraction, allowing determination of structural features at atomic resolution.

The function of these channels is explored by electrophysiological studies.

Genetic approaches include screening for behavioral changes in animals with mutations in K+ channel genes. Such genetic methods allowed the genetic identification of the "Shaker" K+ channel gene in Drosophila before ion channel gene sequences were well known.

Study of the altered properties of voltage-gated K+ channel proteins produced by mutated genes has helped reveal the functional roles of K+ channel protein domains and even individual amino acids within their structures.

Structure
Typically, vertebrate voltage-gated K+ channels are tetramers of four identical subunits arranged as a ring, each contributing to the wall of the trans-membrane K+ pore. Each subunit is composed of six membrane spanning hydrophobic α-helical sequences. The high resolution crystallographic structure of the rat Kvα1.2/β2 channel has recently been solved (Protein Databank Accession Number ), and then refined in a lipid membrane-like environment.

Selectivity
Voltage-gated K+ channels are selective for K+ over other cations such as Na+. There is a selectivity filter at the narrowest part of the transmembrane pore.

Channel mutation studies have revealed the parts of the subunits that are essential for ion selectivity. They include the amino acid sequence (Thr-Val-Gly-Tyr-Gly) or (Thr-Val-Gly-Phe-Gly) typical to the selectivity filter of voltage-gated K+ channels. As K+ passes through the pore, interactions between potassium ions and water molecules are prevented and the K+ interacts with specific atomic components of the Thr-Val-Gly-X-Gly sequences from the four channel subunits.

It seems illogical at first that a channel should be able to allow potassium ions but not the smaller sodium ions through. However in an aqueous environment, potassium and sodium cations are solvated by water molecules. When moving through the selectivity filter of the potassium channel, these solvated water molecules are replaced by backbone carbonyl groups of the channel protein. The diameter of the selectivity filter is ideal for the potassium cation, but too big for the smaller sodium cation. Hence the potassium cations are well "solvated" by the protein carbonyl groups, but these same carbonyl groups are too far apart to adequately solvate the sodium cation. Hence the passage of potassium cations through this selectivity filter is strongly favored over sodium cations.

Open and closed conformations
Attempts continue to relate the structure of the mammalian voltage-gated K+ channel to its ability to respond to the voltage that exists across the membrane. Specific domains of the channel subunits have been identified that are important for voltage-sensing and converting between the open conformation of the channel and closed conformations. There are at least two closed conformations; in one, the channel can open if the membrane potential becomes positive inside. Voltage-gated K+ channels inactivate after opening, entering a distinctive, second closed conformation. In the inactivated conformation, the channel cannot open, even if the transmembrane voltage is favorable. The amino terminal domain of the K+ channel or an auxiliary protein can mediate "N-type" inactivation. The former has been described as a "ball and chain" model where the N-terminus of the protein forms a ball which is tethered to the rest of the protein through a loop (the chain). The tethered ball is transiently sucked into the inner porehole, preventing ion movement through the channel.