KCNA1
Encyclopedia
Potassium 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.
s).
with periodic ataxia).
is believed to have six domains (S1-S6) with the loop between S5 and S6 forming the channel pore. This region also has a conserved selectivity filter motif. The functional channel is a homotetramer. The N-terminus of the protein associates with β subunits. These subunits regulate channel inactivation as well as its expression. The C-terminus is associated with a PDZ domain
protein which is involved in channel targeting.
s acting on RNA (ADARs) that specifically recognize adenosines within double-stranded regions of pre-mRNAs (e.g. Potassium channel RNA editing signal
) and deaminate them to inosine
. Inosines are recognised as guanosine by the cells translational machinery. There are three members of the ADAR family ADARs 1-3 with ADAR1
and ADAR2
being the only enzymatically active members. ADAR3
is thought to have a regulatory role in the brain. ADAR1 and ADAR2 are widely expressed in tissues while ADAR3 is restricted to the brain. The double stranded regions of RNA are formed by base-pairing between residues in the region close to the editing site with residues usually in a neighboring intron but can sometimes be an exonic sequence too. The region that base pairs with the editing region is known as an Editing Complementary Sequence (ECS).
region found which corresponds to the inner vestibule of the pore. A stem loop hairpin structure mediates the RNA editing. ADAR2
is likely to be the preferred editing enzyme at the I/V site. Editing results in a codon alteration from ATT to GTT resulting in an amino acid change from isoleucine
to valine
. ADAR2 enzyme is the major editing enzyme. The MFOLD programme predicted that the minimum region required for editing would form an imperfect inverted repeat hairpin
. This region is composed of a 114 base pairs. Similar regions have been identified in mouse and rat. The edited adenosine is found in a 6 base pair duplex region. Mutation experiment in the region near the 6 base pair duplex have shown that the specific bases in this region were also essential for editing to occur. The region required for editing is unusual in that the hairpin structure is formed by exon
ic sequences only. In the majority of A to I editng the ECS is found within an intron
ic sequence.
, 68% in the spinal cord
, and 77% in the medulla
.
Editing results in a codon (I/V) change from (ATT) to (GTT) resulting in translation of a valine
instead of a isoleucine
at the position of the editing site. Valine has a larger side chain. RNA editing at this position occurs at a highly conserved ion conducting pore of the channel.This may effect the channels role in the process of fast inactivation.
Voltage-dependent potassium channels modulate excitability by opening and closing a potassium selective pore in response to voltage. The flow of potassium ions is interrupted by interaction of a inactivating particle, an auxiliary protein in humans but an intrinsic part of the channel in other species. The I to V amino acid change is thought to disrupt the hydrophobic interaction between the inactivating particle and the pore lining. This interrupts the process of fast inactivation. Activation kinetics are unaffected by RNA editing. Changes in inactivation kinetics have an impact on the duration and frequency of the action potential. An edited channel passes more current and has a shorter action potential than the non edited type due to the inability of the inactivating particle to interact with the residue in the ion conducting pore of the channel.This was determined by electrophysiology analysis. The length of time the membrane is depolarised is decreased which also reduces the efficiency of transmitter release. Since editing can cause amino acid changes in 1- 4 in potassium channel tetramers, it can have a wide variety of effects on channel inactivation.
Shaker gene
The shaker gene, when mutated, causes a variety of atypical behaviors in the fruit fly, Drosophila melanogaster. Under ether anesthesia, the fly’s legs will shake ; even when the fly is unanaesthetized, it will exhibit aberrant movements...
voltage-gated potassium channel
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....
that in humans is encoded by the KCNA1 gene
Gene
A gene is a molecular unit of heredity of a living organism. It is a name given to some stretches of DNA and RNA that code for a type of protein or for an RNA chain that has a function in the organism. Living beings depend on genes, as they specify all proteins and functional RNA chains...
. The Isaacs syndrome is a result of an autoimmune reaction against the Kv1.1 ion channel.
Genomics
The gene is located on the Watson (plus) strand of the short arm of chromosome 12 (12p13.32). The gene itself is 8,348 bases in length and encodes a protein of 495 amino acids (predicted molecular weight 56.466 kiloDaltonDalton
Dalton may refer to:-In Canada:* Dalton, Algoma District, Ontario* Dalton Armoury, a Canadian Forces facility primarily used by the Queen's Own Rifles of Canada- In the United Kingdom :* Dalton, Cumbria, England* Dalton, Dumfries and Galloway, Scotland...
s).
Alternative names
The recommended name for this protein is potassium voltage-gated channel subfamily A member 1 but a number of alternatives have been used in the literature including HuK1 (human K+ channel I), RBK1 (rubidium potassium channel 1), MBK (mouse brain K+ channel), voltage gated potassium channel HBK1, voltage gated potassium channel subunit Kv1.1, voltage-gated K+ channel HuKI and AEMK (associated with myokymiaMyokymia
Myokymia, is an involuntary, spontaneous, localized quivering of a few muscles bundles within a muscle, but which are insufficient to move a joint.One type is superior oblique myokymia....
with periodic ataxia).
Structure
The proteinProtein
Proteins are biochemical compounds consisting of one or more polypeptides typically folded into a globular or fibrous form, facilitating a biological function. A polypeptide is a single linear polymer chain of amino acids bonded together by peptide bonds between the carboxyl and amino groups of...
is believed to have six domains (S1-S6) with the loop between S5 and S6 forming the channel pore. This region also has a conserved selectivity filter motif. The functional channel is a homotetramer. The N-terminus of the protein associates with β subunits. These subunits regulate channel inactivation as well as its expression. The C-terminus is associated with a PDZ domain
PDZ domain
The PDZ domain is a common structural domain of 80-90 amino-acids found in the signaling proteins of bacteria, yeast, plants, viruses and animals...
protein which is involved in channel targeting.
Function
The protein functions as a potassium selective channel through which the potassium ion may pass through in consensus with the electrochemical gradient. They play a role in repolarisation of membranes.Type
A to I RNA editing is catalyzed by a family of adenosine deaminaseAdenosine deaminase
Adenosine deaminase is an enzyme involved in purine metabolism. It is needed for the breakdown of adenosine from food and for the turnover of nucleic acids in tissues.-Reactions:...
s acting on RNA (ADARs) that specifically recognize adenosines within double-stranded regions of pre-mRNAs (e.g. Potassium channel RNA editing signal
Potassium channel RNA editing signal
The potassium channel RNA editing signal is an RNA element found in human Kv1.1 and its homologues which directs the efficient modification of an adenosine to inosine by an adenosine deaminase acting on RNA . The ADAR modification causes an isoleucine/valine recoding event which lies in the...
) and deaminate them to inosine
Inosine
Inosine is a nucleoside that is formed when hypoxanthine is attached to a ribose ring via a β-N9-glycosidic bond....
. Inosines are recognised as guanosine by the cells translational machinery. There are three members of the ADAR family ADARs 1-3 with ADAR1
ADAR
Double-stranded RNA-specific adenosine deaminase is an enzyme that in humans is encoded by the ADAR gene.-Further reading:...
and ADAR2
ADARB1
Double-stranded RNA-specific editase 1 is an enzyme that in humans is encoded by the ADARB1 gene.ADAR2 requires the small molecule inositol hexakisphosphate for proper function.-Further reading:...
being the only enzymatically active members. ADAR3
ADARB2
Double-stranded RNA-specific editase B2 is an enzyme that in humans is encoded by the ADARB2 gene.-Further reading:...
is thought to have a regulatory role in the brain. ADAR1 and ADAR2 are widely expressed in tissues while ADAR3 is restricted to the brain. The double stranded regions of RNA are formed by base-pairing between residues in the region close to the editing site with residues usually in a neighboring intron but can sometimes be an exonic sequence too. The region that base pairs with the editing region is known as an Editing Complementary Sequence (ECS).
Location
The modified residue is found at amino acid 400 of the final protein. This is located in the sixth transmembraneTransmembrane protein
A transmembrane protein is a protein that goes from one side of a membrane through to the other side of the membrane. Many TPs function as gateways or "loading docks" to deny or permit the transport of specific substances across the biological membrane, to get into the cell, or out of the cell as...
region found which corresponds to the inner vestibule of the pore. A stem loop hairpin structure mediates the RNA editing. ADAR2
ADARB1
Double-stranded RNA-specific editase 1 is an enzyme that in humans is encoded by the ADARB1 gene.ADAR2 requires the small molecule inositol hexakisphosphate for proper function.-Further reading:...
is likely to be the preferred editing enzyme at the I/V site. Editing results in a codon alteration from ATT to GTT resulting in an amino acid change from isoleucine
Isoleucine
Isoleucine is an α-amino acid with the chemical formula HO2CCHCHCH2CH3. It is an essential amino acid, which means that humans cannot synthesize it, so it must be ingested. Its codons are AUU, AUC and AUA....
to valine
Valine
Valine is an α-amino acid with the chemical formula HO2CCHCH2. L-Valine is one of 20 proteinogenic amino acids. Its codons are GUU, GUC, GUA, and GUG. This essential amino acid is classified as nonpolar...
. ADAR2 enzyme is the major editing enzyme. The MFOLD programme predicted that the minimum region required for editing would form an imperfect inverted repeat hairpin
Stem-loop
Stem-loop intramolecular base pairing is a pattern that can occur in single-stranded DNA or, more commonly, in RNA. The structure is also known as a hairpin or hairpin loop. It occurs when two regions of the same strand, usually complementary in nucleotide sequence when read in opposite directions,...
. This region is composed of a 114 base pairs. Similar regions have been identified in mouse and rat. The edited adenosine is found in a 6 base pair duplex region. Mutation experiment in the region near the 6 base pair duplex have shown that the specific bases in this region were also essential for editing to occur. The region required for editing is unusual in that the hairpin structure is formed by exon
Exon
An exon is a nucleic acid sequence that is represented in the mature form of an RNA molecule either after portions of a precursor RNA have been removed by cis-splicing or when two or more precursor RNA molecules have been ligated by trans-splicing. The mature RNA molecule can be a messenger RNA...
ic sequences only. In the majority of A to I editng the ECS is found within an intron
Intron
An intron is any nucleotide sequence within a gene that is removed by RNA splicing to generate the final mature RNA product of a gene. The term intron refers to both the DNA sequence within a gene, and the corresponding sequence in RNA transcripts. Sequences that are joined together in the final...
ic sequence.
Conservation
The editing is highly conserved having been observed in squid, fruit fly, mouse and rat.Regulation
Editing levels vary in different tissues: 17% in the caudate nucleusCaudate nucleus
The caudate nucleus is a nucleus located within the basal ganglia of the brains of many animal species. The caudate nucleus is an important part of the brain's learning and memory system.-Anatomy:...
, 68% in the spinal cord
Spinal cord
The spinal cord is a long, thin, tubular bundle of nervous tissue and support cells that extends from the brain . The brain and spinal cord together make up the central nervous system...
, and 77% in the medulla
Medulla
Medulla refers to the middle of something and derives from the Latin word for marrow. Its anatomical uses include:* Medulla oblongata, a part of the brain stem* Renal medulla, a part of the kidney* Adrenal medulla, a part of the adrenal gland...
.
Structure
Editing results in a codon (I/V) change from (ATT) to (GTT) resulting in translation of a valine
Valine
Valine is an α-amino acid with the chemical formula HO2CCHCH2. L-Valine is one of 20 proteinogenic amino acids. Its codons are GUU, GUC, GUA, and GUG. This essential amino acid is classified as nonpolar...
instead of a isoleucine
Isoleucine
Isoleucine is an α-amino acid with the chemical formula HO2CCHCHCH2CH3. It is an essential amino acid, which means that humans cannot synthesize it, so it must be ingested. Its codons are AUU, AUC and AUA....
at the position of the editing site. Valine has a larger side chain. RNA editing at this position occurs at a highly conserved ion conducting pore of the channel.This may effect the channels role in the process of fast inactivation.
Function
Voltage-dependent potassium channels modulate excitability by opening and closing a potassium selective pore in response to voltage. The flow of potassium ions is interrupted by interaction of a inactivating particle, an auxiliary protein in humans but an intrinsic part of the channel in other species. The I to V amino acid change is thought to disrupt the hydrophobic interaction between the inactivating particle and the pore lining. This interrupts the process of fast inactivation. Activation kinetics are unaffected by RNA editing. Changes in inactivation kinetics have an impact on the duration and frequency of the action potential. An edited channel passes more current and has a shorter action potential than the non edited type due to the inability of the inactivating particle to interact with the residue in the ion conducting pore of the channel.This was determined by electrophysiology analysis. The length of time the membrane is depolarised is decreased which also reduces the efficiency of transmitter release. Since editing can cause amino acid changes in 1- 4 in potassium channel tetramers, it can have a wide variety of effects on channel inactivation.