JavaScript is disabled in your browser. Please enable JavaScript to view this website.

Kcna1

Domain

The cytoplasmic N-terminus is important for tetramerization and for interaction with the beta subunits that promote rapid channel closure.

The transmembrane segment S4 functions as a 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.

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:10191303, PubMed:12611922, PubMed:21966978, PubMed:22158511, PubMed:23473320, PubMed:9581771, PubMed:9736643). Forms tetrameric potassium-selective channels through which potassium ions pass in accordance with their electrochemical gradient. The channel alternates between opened and closed conformations in response to the voltage difference across the membrane (PubMed:15361858). 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. 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:15361858). 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:15361858, PubMed:7517498). In contrast, a heterotetrameric channel formed by KCNA1 and KCNA4 shows rapid inactivation (By similarity). Regulates neuronal excitability in hippocampus, especially in mossy fibers and medial perforant path axons, preventing neuronal hyperexcitability (PubMed:23466697). May function as down-stream effector for G protein-coupled receptors and inhibit GABAergic inputs to basolateral amygdala neurons (By similarity). May contribute to the regulation of neurotransmitter release, such as gamma-aminobutyric acid (GABA) release (By similarity). 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 (PubMed:20392939, PubMed:22641786, PubMed:25377007). Required for normal neuromuscular responses (PubMed:9736643). 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 (PubMed:23473320). Required for normal responses to auditory stimuli and precise location of sound sources, but not for sound perception (PubMed:21966978, PubMed:22396426). The use of toxins that block specific channels suggest that it contributes to the regulation of the axonal release of the neurotransmitter dopamine (PubMed:21233214). Required for normal postnatal brain development and normal proliferation of neuronal precursor cells in the brain (PubMed:17250763, PubMed:17315199, PubMed:22411008, PubMed:8995755). 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).

Involvement in disease

A spontaneous mutation leading to a frameshift and truncation of Kcna2 causes megencephaly with a 25% increase of brain weight relative to wild-type. Especially the hippocampus shows increased proliferation of neurons and astrocytes, leading to increased brain volume (PubMed:17315199). Mutant mice appear normal at birth. After 3-4 weeks, they display low body weight, a subtle shakiness in their gait, a preference for a strange sitting position that is maintained for periods ranging from 30 seconds to several minutes, excessive lacrimation and acoustic startle hypersensitivity (PubMed:21966978, PubMed:8995755). The increase in the acoustic startle response is down-regulated by treatment with the anti-epileptic drug valproate (PubMed:21966978). Mutant mice display an abnormal electro-encephalogram with single spikes and waves, when anesthesized (PubMed:21966978). The electric activity of mossy cells from the dentate hilus region is altered and shows increased firing of action potentials, probably due to the absence of functional Kcna1 channels (PubMed:14686897). Heterozygotes show mechanical allodynia, but no increased sensitivity to heat (PubMed:23473320). Homozygotes show no alteration of the islet of Langerhans structure, of the basal levels of insulin secretion and blood glucose levels (PubMed:21483673). Compared to wild-type, they display moderately increased insulin secretion in response to a glucose stimulus (PubMed:21483673). Besides, the frequency of beta cell action potentials is increased (PubMed:21483673).

Post-translational modifications

N-glycosylated.

Palmitoylated on Cys-243; which may be required for membrane targeting.

Phosphorylated on tyrosine residues. Phosphorylation increases in response to NRG1; this inhibits channel activity (PubMed:22158511). Phosphorylation at Ser-446 regulates channel activity by down-regulating expression at the cell membrane (By similarity).

Sequence Similarities

Belongs to the potassium channel family. A (Shaker) (TC 1.A.1.2) subfamily. Kv1.1/KCNA1 sub-subfamily.

Tissue Specificity

Detected in brain (PubMed:21483673, PubMed:22158511, PubMed:2451788, PubMed:9581771). Expressed in cerebellar cortex basket cell terminals, the area surround the Purkinje cell soma, and the pinceaux expansions encircling the axon initial segment (at protein level) (PubMed:26269648). Detected in the juxtaparanodal regions of the nodes of Ranvier in myelinated axons (PubMed:8046438, PubMed:8361541). Detected in the paranodal region in sciatic nerve (PubMed:9736643). Detected on cell bodies in cerebellum, dorsal and ventral cochlear nucleus, pontine reticular nucleus, mesencephalic trigeminal nucleus, motor trigeminal nucleus and the pricipal sensory trigeminal nucleus (PubMed:8046438). Detected in terminal fields of basket cells in the cerebellum corpus medullare (PubMed:8046438, PubMed:8361541, PubMed:9581771). Detected in hippocampus CA3 pyramidal neurons and in the hilus and stratum moleculare of the dentate gyrus (PubMed:14686897, PubMed:8046438, PubMed:9581771). Detected in the central nucleus and the external nucleus of the inferior colliculus (PubMed:21966978, PubMed:8046438). Detected in fiber tracts in the optic tract, external medullary lamina, stria terminalis, medulla, ventral pallidum and substantia nigra (PubMed:8046438). Detected in neurons from dorsal root ganglion (PubMed:23473320). Detected in neurons in the medial nucleus of the trapezoid body (PubMed:12611922). Detected in midbrain dopamine neuron axon terminals (PubMed:21233214). Detected in brain cortex (PubMed:14686897, PubMed:8046438). Detected in brainstem (PubMed:8361541). Detected in juxtaparanodal regions of the nodes of Ranvier in the vagus nerve, but only at very low levels in the heart (PubMed:20392939, PubMed:22641786). Detected in the islet of Langerhans (PubMed:21483673). Detected at the luminal membrane in distal convoluted tubules in the kidney (at protein level) (PubMed:19307729). Detected in hippocampus, thalamus, neocortex and ventral brain cortex, including the piriform and entorhinal cortex and the amygdala (PubMed:14686897). Detected in midbrain dopamine neurons (PubMed:21233214). Detected in heart atrium, ventricle, sinoatrial node and atrioventricular node (PubMed:20392939).

Cellular localization

Alternative names

Potassium voltage-gated channel subfamily A member 1, MBK1, MKI, Voltage-gated potassium channel subunit Kv1.1, Kcna1

swissprot:P16388