Voltage-gated potassium channel
Encyclopedia
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.
. These subunits do not conduct current on their own but rather modulate the activity of Kv channels.
Proteins minK and MiRP1 are putative hERG beta subunits.
s 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.
. 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 .
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 subunitshttp://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Search&db=books&doptcmdl=GenBookHL&term=potassium+channel+AND+stryer%5Bbook%5D+AND+215962%5Buid%5D&rid=stryer.figgrp.1824.
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.
Potassium channel
In the field of cell biology, potassium channels are the most widely distributed type of ion channel and are found in virtually all living organisms. They form potassium-selective pores that span cell membranes...
and sensitive to voltage changes
Voltage-gated ion channel
Voltage-gated ion channels are a class of transmembrane ion channels that are activated by changes in electrical potential difference near the channel; these types of ion channels are especially critical in neurons, but are common in many types of cells....
in the cell's membrane potential
Membrane potential
Membrane potential is the difference in electrical potential between the interior and exterior of a biological cell. All animal cells are surrounded by a plasma membrane composed of a lipid bilayer with a variety of types of proteins embedded in it...
. 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 (KCNA1KCNA1Potassium voltage-gated channel subfamily A member 1 also known as Kv1.1 is a shaker related voltage-gated potassium channel that in humans is encoded by the KCNA1 gene. The Isaacs syndrome is a result of an autoimmune reaction against the Kv1.1 ion channel.- Genomics :The gene is located on the...
), Kv1.2 (KCNA2KCNA2Potassium voltage-gated channel subfamily A member 2 also known as Kv1.2 is a protein that in humans is encoded by the KCNA2 gene.-Interactions:KCNA2 has been shown to interact with KCNA4, DLG4, PTPRA, KCNAB2, RHOA and Cortactin....
), Kv1.3 (KCNA3KCNA3Potassium voltage-gated channel, shaker-related subfamily, member 3, also known as KCNA3 or Kv1.3, is a protein which in humans is encoded by the KCNA3 gene....
), Kv1.5 (KCNA5KCNA5Potassium voltage-gated channel, shaker-related subfamily, member 5, also known as KCNA5 or Kv1.5, is a protein that in humans is encoded by the KCNA5 gene.-Function:...
), Kv1.6 (KCNA6KCNA6Potassium voltage-gated channel subfamily A member 6 also known as Kv1.6 is a protein that in humans is encoded by the KCNA6 gene. The protein encoded by this gene is a voltage-gated potassium channel subunit....
), Kv1.7 (KCNA7KCNA7Potassium voltage-gated channel subfamily A member 7 also known as Kv1.7 is a protein that in humans is encoded by the KCNA7 gene. The protein encoded by this gene is a voltage-gated potassium channel subunit. It may contribute to the cardiac transient outward potassium current , the main...
), Kv1.8 (KCNA10KCNA10Potassium voltage-gated channel subfamily A member 10 also known as Kv1.8 is a protein that in humans is encoded by the KCNA10 gene. The protein encoded by this gene is a voltage-gated potassium channel subunit....
) - Kvα2.x - Shab-related: Kv2.1 (KCNB1KCNB1Potassium voltage-gated channel, Shab-related subfamily, member 1, also known as KCNB1 or Kv2.1, is a protein which in humans is encoded by the KCNB1 gene.-Species and tissue distribution:...
), Kv2.2 (KCNB2KCNB2Potassium voltage-gated channel subfamily B member 2 is a protein that in humans is encoded by the KCNB2 gene. The protein encoded by this gene is a voltage-gated potassium channel subunit....
) - Kvα3.x - Shaw-related: Kv3.1 (KCNC1KCNC1Potassium voltage-gated channel subfamily C member 1 is a protein that in humans is encoded by the KCNC1 gene.The Shaker gene family of Drosophila encodes components of voltage-gated potassium channels and comprises four subfamilies. Based on sequence similarity, this gene is similar to one of...
), Kv3.2 (KCNC2KCNC2Potassium voltage-gated channel subfamily C member 2 is a protein that in humans is encoded by the KCNC2 gene. The protein encoded by this gene is a voltage-gated potassium channel subunit.-Expression pattern:...
) - Kvα7.x: Kv7.1 (KCNQ1) - KvLQT1KvLQT1Kv7.1 is a potassium channel protein coded for by the gene KCNQ1. Kv7.1 is present in the cell membranes of cardiac muscle tissue and in inner ear neurons among other tissues...
, Kv7.2 (KCNQ2), Kv7.3 (KCNQ3), Kv7.4 (KCNQ4KCNQ4Potassium voltage-gated channel subfamily KQT member 4 is a protein that in humans is encoded by the KCNQ4 gene.- External links :*...
), Kv7.5 (KCNQ5KCNQ5Potassium voltage-gated channel subfamily KQT member 5 is a protein that in humans is encoded by the KCNQ5 gene.-Further reading:...
) - Kvα10.x: Kv10.1 (KCNH1KCNH1Potassium voltage-gated channel subfamily H member 1 is a protein that in humans is encoded by the KCNH1 gene.- External links :...
)
A-type potassium channel
rapidly inactivating- Kvα1.x - Shaker-related: Kv1.4 (KCNA4KCNA4Potassium voltage-gated channel subfamily A member 4 also known as Kv1.4 is a protein that in humans is encoded by the KCNA4 gene. It contributes to the cardiac transient outward potassium current , the main contributing current to the repolarizing phase 1 of the cardiac action...
) - Kvα3.x - Shaw-related: Kv3.3 (KCNC3KCNC3Potassium voltage-gated channel, Shaw-related subfamily, member 3 also known as KCNC3 or Kv3.3 is a protein which in humans is encoded by the KCNC3.- Function :...
), Kv3.4 (KCNC4KCNC4Potassium voltage-gated channel, Shaw-related subfamily, member 4 , also known as Kv3.4, is a human gene.-Further reading:...
) - Kvα4.x - Shal-related: Kv4.1 (KCND1KCND1Potassium voltage-gated channel, Shal-related subfamily, member 1 , also known as Kv4.1, is a human gene.-Further reading:...
), Kv4.2 (KCND2KCND2Potassium voltage-gated channel subfamily D member 2 is a protein that in humans is encoded by the KCND2 gene. It contributes to the cardiac transient outward potassium current , the main contributing current to the repolarizing phase 1 of the cardiac action...
), Kv4.3 (KCND3KCND3Potassium voltage-gated channel subfamily D member 3 also known as Kv4.3 is a protein that in humans is encoded by the KCND3 gene. It contributes to the cardiac transient outward potassium current , the main contributing current to the repolarizing phase 1 of the cardiac action potential.- Function...
)
Inward-rectifying
Passes current more easily into the inwards direction (Into the cell).- Kvα11.x - ether-a-go-go potassium channels: Kv11.1 (KCNH2) - hERGHERGhERG is a gene that codes for a protein known as Kv11.1 potassium ion channel...
, Kv11.2 (KCNH6KCNH6Potassium voltage-gated channel subfamily H member 6 is a protein that in humans is encoded by the KCNH6 gene. The protein encoded by this gene is a voltage-gated potassium channel subunit....
), Kv11.3 (KCNH7KCNH7Potassium voltage-gated channel subfamily H member 7 is a protein that in humans is encoded by the KCNH7 gene. The protein encoded by this gene is a voltage-gated potassium channel subunit....
)
Slowly activating
- Kvα12.x: Kv12.1 (KCNH8KCNH8Potassium voltage-gated channel subfamily H member 8 is a protein that in humans is encoded by the KCNH8 gene. The protein encoded by this gene is a voltage-gated potassium channel subunit....
), Kv12.2 (KCNH3KCNH3Potassium voltage-gated channel subfamily H member 3 is a protein that in humans is encoded by the KCNH3 gene. The protein encoded by this gene is a voltage-gated potassium channel subunit....
), Kv12.3 (KCNH4KCNH4Potassium voltage-gated channel subfamily H member 4 is a protein that in humans is encoded by the KCNH4 gene. The protein encoded by this gene is a voltage-gated potassium channel subunit....
)
Modifier/silencer
Unable to form functional channels as homotetramers but instead heterotetramerize with Kvα2 family members to form conductive channels.- Kvα5.x: Kv5.1 (KCNF1KCNF1Potassium voltage-gated channel subfamily F member 1 is a protein that in humans is encoded by the KCNF1 gene. The protein encoded by this gene is a voltage-gated potassium channel subunit....
) - Kvα6.x: Kv6.1 (KCNG1KCNG1Potassium voltage-gated channel subfamily G member 1 is a protein that in humans is encoded by the KCNG1 gene....
), Kv6.2 (KCNG2KCNG2Potassium voltage-gated channel subfamily G member 2 is a protein that in humans is encoded by the KCNG2 gene. The protein encoded by this gene is a voltage-gated potassium channel subunit....
), Kv6.3 (KCNG3KCNG3Potassium voltage-gated channel subfamily G member 3 is a protein that in humans is encoded by the KCNG3 gene. The protein encoded by this gene is a voltage-gated potassium channel subunit....
), Kv6.4 (KCNG4KCNG4Potassium voltage-gated channel subfamily G member 4 is a protein that in humans is encoded by the KCNG4 gene. The protein encoded by this gene is a voltage-gated potassium channel subunit....
) - Kvα8.x: Kv8.1 (KCNV1KCNV1Potassium voltage-gated channel subfamily V member 1 is a protein that in humans is encoded by the KCNV1 gene. The protein encoded by this gene is a voltage-gated potassium channel subunit....
), Kv8.2 (KCNV2KCNV2Potassium voltage-gated channel subfamily V member 2 is a protein that in humans is encoded by the KCNV2 gene. The protein encoded by this gene is a voltage-gated potassium channel subunit....
) - Kvα9.x: Kv9.1 (KCNS1KCNS1Potassium voltage-gated channel subfamily S member 1 is a protein that in humans is encoded by the KCNS1 gene. The protein encoded by this gene is a voltage-gated potassium channel subunit....
), Kv9.2 (KCNS2KCNS2Potassium voltage-gated channel subfamily S member 2 is a protein that in humans is encoded by the KCNS2 gene. The protein encoded by this gene is a voltage-gated potassium channel subunit....
), Kv9.3 (KCNS3KCNS3Potassium voltage-gated channel subfamily S member 3 is a protein that in humans is encoded by the KCNS3 gene.-Further reading:...
)
Beta subunits
Beta subunits are auxiliary proteins that associate with alpha subunits, sometimes in a α4β4 stoichiometryStoichiometry
Stoichiometry is a branch of chemistry that deals with the relative quantities of reactants and products in chemical reactions. In a balanced chemical reaction, the relations among quantities of reactants and products typically form a ratio of whole numbers...
. These subunits do not conduct current on their own but rather modulate the activity of Kv channels.
- Kvβ1 (KCNAB1KCNAB1Voltage-gated potassium channel subunit beta-1 is a protein that in humans is encoded by the KCNAB1 gene....
) - Kvβ2 (KCNAB2KCNAB2Voltage-gated potassium channel subunit beta-2 is a protein that in humans is encoded by the KCNAB2 gene.- External links :...
) - Kvβ3 (KCNAB3KCNAB3Voltage-gated potassium channel subunit beta-3 is a protein that in humans is encoded by the KCNAB3 gene. The protein encoded by this gene is a voltage-gated potassium channel beta subunit....
) - minK (KCNE1KCNE1Potassium voltage-gated channel subfamily E member 1 is a protein that in humans is encoded by the KCNE1 gene.KCNE1 is a gene associated with Long QT syndrome type 5. It can both cause Romano-Wards syndrome and Jervell Lange-Nielsens syndrome -External links:*...
) - MiRP1 (KCNE2KCNE2Potassium voltage-gated channel subfamily E member 2 is a protein that in humans is encoded by the KCNE2 gene. The protein encoded by this gene is a voltage-gated potassium channel accessory subunit associated with Long QT syndrome....
) - MiRP2KCNE3Potassium voltage-gated channel, Isk-related family, member 3, also known as KCNE3, is a protein that in humans is encoded by the KCNE3 gene.- Function :...
(KCNE3KCNE3Potassium voltage-gated channel, Isk-related family, member 3, also known as KCNE3, is a protein that in humans is encoded by the KCNE3 gene.- Function :...
) - MiRP3 (KCNE4KCNE4Potassium voltage-gated channel subfamily E member 4 is a protein that in humans is encoded by the KCNE4 gene....
) - KCNE1-like (KCNE1LKCNE1LKCNE1-like also known as KCNE1L is a protein that in humans is encoded by the KCNE1L gene.-Function:Voltage-gated potassium channels represent the most complex class of voltage-gated ion channels from both functional and structural standpoints...
) - KCNIP1 (KCNIP1KCNIP1Kv channel-interacting protein 1 also known as KChIP1 is a protein that in humans is encoded by the KCNIP1 gene.- Function :This gene encodes a member of the family of voltage-gated potassium channel-interacting proteins , which belong to the recoverin branch of the EF-hand superfamily...
) - KCNIP2KCNIP2Kv channel-interacting protein 2 also known as KChIP2 is a protein that in humans is encoded by the KCNIP2 gene.- Function :This gene encodes a member of the family of voltage-gated potassium channel-interacting proteins , which belong to the recoverin branch of the EF-hand superfamily...
(KCNIP2KCNIP2Kv channel-interacting protein 2 also known as KChIP2 is a protein that in humans is encoded by the KCNIP2 gene.- Function :This gene encodes a member of the family of voltage-gated potassium channel-interacting proteins , which belong to the recoverin branch of the EF-hand superfamily...
) - KCNIP3 (KCNIP3)
- KCNIP4 (KCNIP4KCNIP4Kv channel-interacting protein 4 is a protein that in humans is encoded by the KCNIP4 gene....
)
Proteins minK and MiRP1 are putative hERG beta subunits.
Animal research
The voltage-gated K+ channels that provide the outward currents of action potentialAction potential
In physiology, an action potential is a short-lasting event in which the electrical membrane potential of a cell rapidly rises and falls, following a consistent trajectory. Action potentials occur in several types of animal cells, called excitable cells, which include neurons, muscle cells, and...
s 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
Electrophysiology
Electrophysiology is the study of the electrical properties of biological cells and tissues. It involves measurements of voltage change or electric current on a wide variety of scales from single ion channel proteins to whole organs like the heart...
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
Drosophila
Drosophila is a genus of small flies, belonging to the family Drosophilidae, whose members are often called "fruit flies" or more appropriately pomace flies, vinegar flies, or wine flies, a reference to the characteristic of many species to linger around overripe or rotting fruit...
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 sequencesAlpha helix
A common motif in the secondary structure of proteins, the alpha helix is a right-handed coiled or spiral conformation, in which every backbone N-H group donates a hydrogen bond to the backbone C=O group of the amino acid four residues earlier...
. 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 subunitshttp://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Search&db=books&doptcmdl=GenBookHL&term=potassium+channel+AND+stryer%5Bbook%5D+AND+215962%5Buid%5D&rid=stryer.figgrp.1824.
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 that 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.See also
- Ion channelIon channelIon channels are pore-forming proteins that help establish and control the small voltage gradient across the plasma membrane of cells by allowing the flow of ions down their electrochemical gradient. They are present in the membranes that surround all biological cells...
- Potassium channel tetramerisation domainPotassium channel tetramerisation domainK+ channel tetramerisation domain is the N-terminal, cytoplasmic tetramerisation domain of voltage-gated K+ channels. It defines molecular determinants for subfamily-specific assembly of alpha-subunits into functional tetrameric channels. It is distantly related to the BTB/POZ domain .-Potassium...
- Ion channel familyIon channel familyTransmembrane ion channel family was defined in InterPro and Pfam as the family of tetrameric sodium, potassium, and calcium ion channels, in which two C-terminal transmembrane helices flank a loop which determines ion selectivity of the channel pore...
External links
- "Voltage-gated potassium channel database (VKCDB)" at ualberta.ca - Spatial positions of voltage gated potassium channels in membranes