UniProt functional annotation for P10499



	UniProt functional annotation for P10499

UniProt code: P10499.

Organism: Rattus norvegicus (Rat).

Taxonomy: Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia; Eutheria; Euarchontoglires; Glires; Rodentia; Myomorpha; Muroidea; Muridae; Murinae; Rattus.

Function: Voltage-gated potassium channel that mediates transmembrane potassium transport in excitable membranes, primarily in the brain and the central nervous system, but also in the kidney. Contributes to the regulation of the membrane potential and nerve signaling, and prevents neuronal hyperexcitability (PubMed:12177193, PubMed:17855588, PubMed:22206926). Forms tetrameric potassium-selective channels through which potassium ions pass in accordance with their electrochemical gradient (PubMed:23725331). The channel alternates between opened and closed conformations in response to the voltage difference across the membrane (PubMed:2539643). Can form functional homotetrameric channels and heterotetrameric channels that contain variable proportions of KCNA1, KCNA2, KCNA4, KCNA5, KCNA6, KCNA7, and possibly other family members as well; channel properties depend on the type of alpha subunits that are part of the channel (PubMed:2348860, PubMed:12177193, PubMed:10896669, PubMed:23725331). Channel properties are modulated by cytoplasmic beta subunits that regulate the subcellular location of the alpha subunits and promote rapid inactivation of delayed rectifier potassium channels (PubMed:10896669, PubMed:12114518). In vivo, membranes probably contain a mixture of heteromeric potassium channel complexes, making it difficult to assign currents observed in intact tissues to any particular potassium channel family member. Homotetrameric KCNA1 forms a delayed-rectifier potassium channel that opens in response to membrane depolarization, followed by slow spontaneous channel closure (PubMed:2348860, PubMed:8038169, PubMed:12681381, PubMed:22206926, PubMed:23725331). In contrast, a heterotetrameric channel formed by KCNA1 and KCNA4 shows rapid inactivation (PubMed:2348860). Regulates neuronal excitability in hippocampus, especially in mossy fibers and medial perforant path axons, preventing neuronal hyperexcitability. Response to toxins that are selective for KCNA1, respectively for KCNA2, suggests that heteromeric potassium channels composed of both KCNA1 and KCNA2 play a role in pacemaking and regulate the output of deep cerebellar nuclear neurons (PubMed:12177193, PubMed:23318870). May function as down-stream effector for G protein-coupled receptors and inhibit GABAergic inputs to basolateral amygdala neurons (PubMed:16306173). May contribute to the regulation of neurotransmitter release, such as gamma-aminobutyric acid (GABA) release (PubMed:17869444). Plays a role in regulating the generation of action potentials and preventing hyperexcitability in myelinated axons of the vagus nerve, and thereby contributes to the regulation of heart contraction (By similarity). Required for normal neuromuscular responses (PubMed:22206926). Regulates the frequency of neuronal action potential firing in response to mechanical stimuli, and plays a role in the perception of pain caused by mechanical stimuli, but does not play a role in the perception of pain due to heat stimuli (By similarity). Required for normal responses to auditory stimuli and precise location of sound sources, but not for sound perception (By similarity). The use of toxins that block specific channels suggest that it contributes to the regulation of the axonal release of the neurotransmitter dopamine (By similarity). Required for normal postnatal brain development and normal proliferation of neuronal precursor cells in the brain (By similarity). Plays a role in the reabsorption of Mg(2+) in the distal convoluted tubules in the kidney and in magnesium ion homeostasis, probably via its effect on the membrane potential (By similarity). {ECO:0000250|UniProtKB:P16388, ECO:0000250|UniProtKB:Q09470, ECO:0000269|PubMed:10896669, ECO:0000269|PubMed:12114518, ECO:0000269|PubMed:12177193, ECO:0000269|PubMed:12681381, ECO:0000269|PubMed:17855588, ECO:0000269|PubMed:17869444, ECO:0000269|PubMed:22206926, ECO:0000269|PubMed:23318870, ECO:0000269|PubMed:2348860, ECO:0000269|PubMed:23725331, ECO:0000269|PubMed:2539643, ECO:0000269|PubMed:8038169, ECO:0000305|PubMed:16306173}.

Activity regulation: Inhibited by 4-aminopyridine (4-AP) and by tetraethylammonium (TEA) (PubMed:2539643). Inhibited by kaliotoxin (KTX) (PubMed:23725331). {ECO:0000269|PubMed:2348860, ECO:0000269|PubMed:23725331, ECO:0000269|PubMed:2539643}.

Subunit: Homotetramer and heterotetramer with other channel-forming alpha subunits, such as KCNA2, KCNA4, KCNA5, KCNA6 and KCNA7 (PubMed:10896669, PubMed:10884227). Channel activity is regulated by interaction with the beta subunits KCNAB1 and KCNAB2 (PubMed:9334400, PubMed:12114518). Identified in a complex with KCNA2 and KCNAB2 (PubMed:10896669, PubMed:11086297, PubMed:23318870, PubMed:10884227). Interacts (via C-terminus) with the PDZ domains of DLG1, DLG2 and DLG4. Interacts with LGI1 within a complex containing LGI1, KCNA4 and KCNAB1. Interacts (via cytoplasmic N-terminal domain) with KCNRG; this inhibits channel activity (By similarity). Interacts with ANK3; this inhibits channel activity (By similarity). Interacts (via N-terminus) with STX1A; this promotes channel inactivation (PubMed:12114518). Interacts (via N-terminus) with the heterodimer formed by GNB1 and GNG2; this promotes channel inactivation (PubMed:12114518). Can interact simultaneously with STX1A and the heterodimer formed by GNB1 and GNG2 (PubMed:12114518). {ECO:0000250, ECO:0000250|UniProtKB:Q09470, ECO:0000269|PubMed:10884227, ECO:0000269|PubMed:10896669, ECO:0000269|PubMed:11086297, ECO:0000269|PubMed:12114518, ECO:0000269|PubMed:16504945, ECO:0000269|PubMed:23318870, ECO:0000269|PubMed:7477295, ECO:0000269|PubMed:9334400}.

Subcellular location: Cell membrane {ECO:0000269|PubMed:12114518, ECO:0000269|PubMed:12681381, ECO:0000269|PubMed:17855588, ECO:0000269|PubMed:22206926, ECO:0000269|PubMed:2348860, ECO:0000269|PubMed:23725331, ECO:0000269|PubMed:2539643, ECO:0000269|PubMed:8038169}; Multi-pass membrane protein {ECO:0000305}. Membrane {ECO:0000269|PubMed:11086297, ECO:0000269|PubMed:9334400}. Cell projection, axon {ECO:0000269|PubMed:11086297, ECO:0000269|PubMed:12177193, ECO:0000269|PubMed:9334400}. Cytoplasmic vesicle {ECO:0000269|PubMed:12177193, ECO:0000269|PubMed:8038169}. Perikaryon {ECO:0000269|PubMed:12177193}. Endoplasmic reticulum {ECO:0000269|PubMed:10896669, ECO:0000269|PubMed:12681381}. Cell projection, dendrite {ECO:0000250|UniProtKB:P16388}. Cell junction {ECO:0000250|UniProtKB:P16388}. Cell junction, synapse {ECO:0000250|UniProtKB:P16388}. Cell junction, synapse, presynapse {ECO:0000250|UniProtKB:P16388}. Cell junction, synapse, presynaptic cell membrane {ECO:0000269|PubMed:17869444}. Note=Homotetrameric KCNA1 is primarily located in the endoplasmic reticulum. Interaction with KCNA2 and KCNAB2 or with KCNA4 and KCNAB2 promotes expression at the cell membrane (PubMed:10896669). {ECO:0000250|UniProtKB:P16388, ECO:0000269|PubMed:10896669}.

Tissue specificity: Detected in hippocampus, in the middle third of the molecular layer of the dentate gyrus and in stratum radiatum and stratum oriens (PubMed:9334400). Detected in the mossy fiber zone in the hippocampus CA3 region, at or near axon terminals (PubMed:9334400). Detected in brain cortex, at basket cell terminals (PubMed:9334400). Detected adjacent to nodes of Ranvier in juxtaparanodal zones in spinal cord nerve fibers, but also in paranodal regions in some myelinated spinal cord axons (PubMed:11086297). Detected in juxtaparanodal regions adjacent to the nodes of Ranvier in myelinated axons in cerebellar white matter (PubMed:9334400). Detected in sensory neurons (PubMed:17855588). Detected in neurons from the medial nucleus of the trapezoid body (PubMed:12177193). Detected in basolateral amygdala (PubMed:16306173). Detected in the paraventricular nucleus of the hypothalamus (PubMed:17869444). Detected in the islet of Langerhans (at protein level) (PubMed:21483673). Detected in the islet of Langerhans (PubMed:21483673). {ECO:0000269|PubMed:11086297, ECO:0000269|PubMed:12177193, ECO:0000269|PubMed:16306173, ECO:0000269|PubMed:17855588, ECO:0000269|PubMed:21483673, ECO:0000269|PubMed:9334400}.

Domain: The cytoplasmic N-terminus is important for tetramerization and for interaction with the beta subunits that promote rapid channel closure. {ECO:0000269|PubMed:10884227}.

Domain: The transmembrane segment S4 functions as voltage-sensor and is characterized by a series of positively charged amino acids at every third position. Channel opening and closing is effected by a conformation change that affects the position and orientation of the voltage-sensor paddle formed by S3 and S4 within the membrane. A transmembrane electric field that is positive inside would push the positively charged S4 segment outwards, thereby opening the pore, while a field that is negative inside would pull the S4 segment inwards and close the pore. Changes in the position and orientation of S4 are then transmitted to the activation gate formed by the inner helix bundle via the S4-S5 linker region. {ECO:0000250|UniProtKB:P63142}.

Ptm: Palmitoylated on Cys-243; which may be required for membrane targeting. {ECO:0000250|UniProtKB:Q09470}.

Ptm: N-glycosylated. {ECO:0000269|PubMed:10896669, ECO:0000269|PubMed:8038169}.

Ptm: Phosphorylated on tyrosine residues. Phosphorylation increases in response to NRG1; this inhibits channel activity (By similarity). Phosphorylated by PKA (PubMed:8038169, PubMed:12681381). Phosphorylation at Ser-446 regulates channel activity by down- regulating expression at the cell membrane (By similarity). {ECO:0000250|UniProtKB:P16388, ECO:0000250|UniProtKB:Q09470, ECO:0000269|PubMed:12681381, ECO:0000269|PubMed:8038169}.

Rna editing: Modified_positions=400 {ECO:0000269|PubMed:12907802}; Note=Partially edited. RNA editing is at an average of 50% in the whole brain.;

Miscellaneous: A missense mutation at Ser-309 is the cause of the autosomal dominant myokymia and seizures (ADMS) phenotype. Homozygous and heterozygous rats are born at the expected Mendelian rate. After 6 weeks, heterozygous rats begin to display muscle twitching, startle responses and spontaneous convulsive seizures; over 80% of the animals are dead after 30 weeks. After 16 weeks, they display lower body weight compared to wild-type. The rats exhibit severe periodic seizures with characteristic alterations in their cortical and hippocampal electroencephalogram, similar to rodent models of temporal lobe epilepsy. Homozygous rats display impaired development starting 14 days after birth, with reduced body weight, tremors, motor incoordination, spontaneous convulsive seizures; none survive past 18 days after birth. {ECO:0000269|PubMed:22206926}.

Miscellaneous: The delay or D-type current observed in hippocampus pyramidal neurons is probably mediated by potassium channels containing KCNA2 plus KCNA1 or other family members. It is activated at about -50 mV, i.e. below the action potential threshold, and is characterized by slow inactivation, extremely slow recovery from inactivation, sensitivity to dendrotoxin (DTX) and to 4-aminopyridine (4-AP). {ECO:0000305|PubMed:17917103}.

Similarity: Belongs to the potassium channel family. A (Shaker) (TC 1.A.1.2) subfamily. Kv1.1/KCNA1 sub-subfamily. {ECO:0000305}.

Annotations taken from UniProtKB at the EBI.


Organism:		Rattus norvegicus (Rat).
Taxonomy:		Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia; Eutheria; Euarchontoglires; Glires; Rodentia; Myomorpha; Muroidea; Muridae; Murinae; Rattus.



Function:		Voltage-gated potassium channel that mediates transmembrane potassium transport in excitable membranes, primarily in the brain and the central nervous system, but also in the kidney. Contributes to the regulation of the membrane potential and nerve signaling, and prevents neuronal hyperexcitability (PubMed:12177193, PubMed:17855588, PubMed:22206926). Forms tetrameric potassium-selective channels through which potassium ions pass in accordance with their electrochemical gradient (PubMed:23725331). The channel alternates between opened and closed conformations in response to the voltage difference across the membrane (PubMed:2539643). Can form functional homotetrameric channels and heterotetrameric channels that contain variable proportions of KCNA1, KCNA2, KCNA4, KCNA5, KCNA6, KCNA7, and possibly other family members as well; channel properties depend on the type of alpha subunits that are part of the channel (PubMed:2348860, PubMed:12177193, PubMed:10896669, PubMed:23725331). Channel properties are modulated by cytoplasmic beta subunits that regulate the subcellular location of the alpha subunits and promote rapid inactivation of delayed rectifier potassium channels (PubMed:10896669, PubMed:12114518). In vivo, membranes probably contain a mixture of heteromeric potassium channel complexes, making it difficult to assign currents observed in intact tissues to any particular potassium channel family member. Homotetrameric KCNA1 forms a delayed-rectifier potassium channel that opens in response to membrane depolarization, followed by slow spontaneous channel closure (PubMed:2348860, PubMed:8038169, PubMed:12681381, PubMed:22206926, PubMed:23725331). In contrast, a heterotetrameric channel formed by KCNA1 and KCNA4 shows rapid inactivation (PubMed:2348860). Regulates neuronal excitability in hippocampus, especially in mossy fibers and medial perforant path axons, preventing neuronal hyperexcitability. Response to toxins that are selective for KCNA1, respectively for KCNA2, suggests that heteromeric potassium channels composed of both KCNA1 and KCNA2 play a role in pacemaking and regulate the output of deep cerebellar nuclear neurons (PubMed:12177193, PubMed:23318870). May function as down-stream effector for G protein-coupled receptors and inhibit GABAergic inputs to basolateral amygdala neurons (PubMed:16306173). May contribute to the regulation of neurotransmitter release, such as gamma-aminobutyric acid (GABA) release (PubMed:17869444). Plays a role in regulating the generation of action potentials and preventing hyperexcitability in myelinated axons of the vagus nerve, and thereby contributes to the regulation of heart contraction (By similarity). Required for normal neuromuscular responses (PubMed:22206926). Regulates the frequency of neuronal action potential firing in response to mechanical stimuli, and plays a role in the perception of pain caused by mechanical stimuli, but does not play a role in the perception of pain due to heat stimuli (By similarity). Required for normal responses to auditory stimuli and precise location of sound sources, but not for sound perception (By similarity). The use of toxins that block specific channels suggest that it contributes to the regulation of the axonal release of the neurotransmitter dopamine (By similarity). Required for normal postnatal brain development and normal proliferation of neuronal precursor cells in the brain (By similarity). Plays a role in the reabsorption of Mg(2+) in the distal convoluted tubules in the kidney and in magnesium ion homeostasis, probably via its effect on the membrane potential (By similarity). {ECO:0000250\|UniProtKB:P16388, ECO:0000250\|UniProtKB:Q09470, ECO:0000269\|PubMed:10896669, ECO:0000269\|PubMed:12114518, ECO:0000269\|PubMed:12177193, ECO:0000269\|PubMed:12681381, ECO:0000269\|PubMed:17855588, ECO:0000269\|PubMed:17869444, ECO:0000269\|PubMed:22206926, ECO:0000269\|PubMed:23318870, ECO:0000269\|PubMed:2348860, ECO:0000269\|PubMed:23725331, ECO:0000269\|PubMed:2539643, ECO:0000269\|PubMed:8038169, ECO:0000305\|PubMed:16306173}.


Activity regulation:		Inhibited by 4-aminopyridine (4-AP) and by tetraethylammonium (TEA) (PubMed:2539643). Inhibited by kaliotoxin (KTX) (PubMed:23725331). {ECO:0000269\|PubMed:2348860, ECO:0000269\|PubMed:23725331, ECO:0000269\|PubMed:2539643}.
Subunit:		Homotetramer and heterotetramer with other channel-forming alpha subunits, such as KCNA2, KCNA4, KCNA5, KCNA6 and KCNA7 (PubMed:10896669, PubMed:10884227). Channel activity is regulated by interaction with the beta subunits KCNAB1 and KCNAB2 (PubMed:9334400, PubMed:12114518). Identified in a complex with KCNA2 and KCNAB2 (PubMed:10896669, PubMed:11086297, PubMed:23318870, PubMed:10884227). Interacts (via C-terminus) with the PDZ domains of DLG1, DLG2 and DLG4. Interacts with LGI1 within a complex containing LGI1, KCNA4 and KCNAB1. Interacts (via cytoplasmic N-terminal domain) with KCNRG; this inhibits channel activity (By similarity). Interacts with ANK3; this inhibits channel activity (By similarity). Interacts (via N-terminus) with STX1A; this promotes channel inactivation (PubMed:12114518). Interacts (via N-terminus) with the heterodimer formed by GNB1 and GNG2; this promotes channel inactivation (PubMed:12114518). Can interact simultaneously with STX1A and the heterodimer formed by GNB1 and GNG2 (PubMed:12114518). {ECO:0000250, ECO:0000250\|UniProtKB:Q09470, ECO:0000269\|PubMed:10884227, ECO:0000269\|PubMed:10896669, ECO:0000269\|PubMed:11086297, ECO:0000269\|PubMed:12114518, ECO:0000269\|PubMed:16504945, ECO:0000269\|PubMed:23318870, ECO:0000269\|PubMed:7477295, ECO:0000269\|PubMed:9334400}.
Subcellular location:		Cell membrane {ECO:0000269\|PubMed:12114518, ECO:0000269\|PubMed:12681381, ECO:0000269\|PubMed:17855588, ECO:0000269\|PubMed:22206926, ECO:0000269\|PubMed:2348860, ECO:0000269\|PubMed:23725331, ECO:0000269\|PubMed:2539643, ECO:0000269\|PubMed:8038169}; Multi-pass membrane protein {ECO:0000305}. Membrane {ECO:0000269\|PubMed:11086297, ECO:0000269\|PubMed:9334400}. Cell projection, axon {ECO:0000269\|PubMed:11086297, ECO:0000269\|PubMed:12177193, ECO:0000269\|PubMed:9334400}. Cytoplasmic vesicle {ECO:0000269\|PubMed:12177193, ECO:0000269\|PubMed:8038169}. Perikaryon {ECO:0000269\|PubMed:12177193}. Endoplasmic reticulum {ECO:0000269\|PubMed:10896669, ECO:0000269\|PubMed:12681381}. Cell projection, dendrite {ECO:0000250\|UniProtKB:P16388}. Cell junction {ECO:0000250\|UniProtKB:P16388}. Cell junction, synapse {ECO:0000250\|UniProtKB:P16388}. Cell junction, synapse, presynapse {ECO:0000250\|UniProtKB:P16388}. Cell junction, synapse, presynaptic cell membrane {ECO:0000269\|PubMed:17869444}. Note=Homotetrameric KCNA1 is primarily located in the endoplasmic reticulum. Interaction with KCNA2 and KCNAB2 or with KCNA4 and KCNAB2 promotes expression at the cell membrane (PubMed:10896669). {ECO:0000250\|UniProtKB:P16388, ECO:0000269\|PubMed:10896669}.
Tissue specificity:		Detected in hippocampus, in the middle third of the molecular layer of the dentate gyrus and in stratum radiatum and stratum oriens (PubMed:9334400). Detected in the mossy fiber zone in the hippocampus CA3 region, at or near axon terminals (PubMed:9334400). Detected in brain cortex, at basket cell terminals (PubMed:9334400). Detected adjacent to nodes of Ranvier in juxtaparanodal zones in spinal cord nerve fibers, but also in paranodal regions in some myelinated spinal cord axons (PubMed:11086297). Detected in juxtaparanodal regions adjacent to the nodes of Ranvier in myelinated axons in cerebellar white matter (PubMed:9334400). Detected in sensory neurons (PubMed:17855588). Detected in neurons from the medial nucleus of the trapezoid body (PubMed:12177193). Detected in basolateral amygdala (PubMed:16306173). Detected in the paraventricular nucleus of the hypothalamus (PubMed:17869444). Detected in the islet of Langerhans (at protein level) (PubMed:21483673). Detected in the islet of Langerhans (PubMed:21483673). {ECO:0000269\|PubMed:11086297, ECO:0000269\|PubMed:12177193, ECO:0000269\|PubMed:16306173, ECO:0000269\|PubMed:17855588, ECO:0000269\|PubMed:21483673, ECO:0000269\|PubMed:9334400}.
Domain:		The cytoplasmic N-terminus is important for tetramerization and for interaction with the beta subunits that promote rapid channel closure. {ECO:0000269\|PubMed:10884227}.
Domain:		The transmembrane segment S4 functions as voltage-sensor and is characterized by a series of positively charged amino acids at every third position. Channel opening and closing is effected by a conformation change that affects the position and orientation of the voltage-sensor paddle formed by S3 and S4 within the membrane. A transmembrane electric field that is positive inside would push the positively charged S4 segment outwards, thereby opening the pore, while a field that is negative inside would pull the S4 segment inwards and close the pore. Changes in the position and orientation of S4 are then transmitted to the activation gate formed by the inner helix bundle via the S4-S5 linker region. {ECO:0000250\|UniProtKB:P63142}.
Ptm:		Palmitoylated on Cys-243; which may be required for membrane targeting. {ECO:0000250\|UniProtKB:Q09470}.
Ptm:		N-glycosylated. {ECO:0000269\|PubMed:10896669, ECO:0000269\|PubMed:8038169}.
Ptm:		Phosphorylated on tyrosine residues. Phosphorylation increases in response to NRG1; this inhibits channel activity (By similarity). Phosphorylated by PKA (PubMed:8038169, PubMed:12681381). Phosphorylation at Ser-446 regulates channel activity by down- regulating expression at the cell membrane (By similarity). {ECO:0000250\|UniProtKB:P16388, ECO:0000250\|UniProtKB:Q09470, ECO:0000269\|PubMed:12681381, ECO:0000269\|PubMed:8038169}.
Rna editing:		Modified_positions=400 {ECO:0000269\|PubMed:12907802}; Note=Partially edited. RNA editing is at an average of 50% in the whole brain.;
Miscellaneous:		A missense mutation at Ser-309 is the cause of the autosomal dominant myokymia and seizures (ADMS) phenotype. Homozygous and heterozygous rats are born at the expected Mendelian rate. After 6 weeks, heterozygous rats begin to display muscle twitching, startle responses and spontaneous convulsive seizures; over 80% of the animals are dead after 30 weeks. After 16 weeks, they display lower body weight compared to wild-type. The rats exhibit severe periodic seizures with characteristic alterations in their cortical and hippocampal electroencephalogram, similar to rodent models of temporal lobe epilepsy. Homozygous rats display impaired development starting 14 days after birth, with reduced body weight, tremors, motor incoordination, spontaneous convulsive seizures; none survive past 18 days after birth. {ECO:0000269\|PubMed:22206926}.
Miscellaneous:		The delay or D-type current observed in hippocampus pyramidal neurons is probably mediated by potassium channels containing KCNA2 plus KCNA1 or other family members. It is activated at about -50 mV, i.e. below the action potential threshold, and is characterized by slow inactivation, extremely slow recovery from inactivation, sensitivity to dendrotoxin (DTX) and to 4-aminopyridine (4-AP). {ECO:0000305\|PubMed:17917103}.
Similarity:		Belongs to the potassium channel family. A (Shaker) (TC 1.A.1.2) subfamily. Kv1.1/KCNA1 sub-subfamily. {ECO:0000305}.