الفهرس 
Classification, Physiology, Structure and Sites of K ChannelsOnly 14 pages are availabe for public view
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Abstract
Potassium channels (K) are a diverse and ubiquitous family of membrane proteins present in both excitable and nonexcitable cells. Members of this channel family play critical roles in cellular signaling processes, regulating neurotransmitter release, heart rate, insulin secretion, neuronal excitability, epithelial electrolyte transport, smooth muscle contraction, and cell volume regulation. Precise biophysical properties, subunit stoichiometry, channel assembly and modulation by second messenger and ligands have been addressed.
Potassium channels (K) conduct ions across the cell membrane down the electrochemical gradient for potassium. They contain a K channel signature sequence form the selectivity filter, they either ligand gated or voltage gated which include; voltage-gated, Ca2+ activated, Na+ activated and inward rectifiers K channels.
Structurally potassium channels are classified into three groups; six transmembrane domains TMD one pore group (voltage-gated and Ca2+-activated K channels), two TMD one pore (inward rectifier K+ channels) and four TMD two pore (“leak” K channels; TWIK, TREK, TRAAK and TASK). Each of these groups is further divided into families, which in turn are divided into subfamilies, with several closely related members within most of these subfamilies.
The first Kv channel was cloned from the Shaker mutant of Drosophila melanogaster in 1987. The human ortholog of Shaker K channels is encoded by the gene KCNA1 (Kv1.1). Since the first cloning, several other genes encoding for Kv channels have been identified from many different species. Based on sequence relatedness, Kv channels have been classified in subfamilies by using the abbreviation Kvy.x.
Voltage-gated potassium (Kv) channels are essential for repolarization of action potentials in neurons and cardiac, skeletal, and smooth muscle. Proper functions of human nervous system rely on a mosaic of Kv channels that not only have their properties finely tuned to the physiological needs, but also have their number and distribution precisely arranged to enable the neuronal computations necessary for adequate perception and response.
Kv1 channels are present in hippocampal neuronal dendrites to modulate temporal integration and the action potential after depolarization (ADP) and hence burst firing.
Reduction of Kv1.1-containing potassium channel function reduces the likelihood of action potential propagation failure at axonal branch points of the cerebellar basket cell axon plexus, thereby increasing inhibitory synaptic inputs of Purkinje cells and causing motor dysfunction.
Inactivation of these axonal Kv1 channels accounts for the ability of neuronal depolarization to broaden axonal action potentials and regulate local synaptic transmission in the brain.
While Kv7.2 and Kv7.3 channels seem the major determinant of “M” currents that are inhibited by several neurotransmitters, including acetylcholine (ACh) through the muscarinic receptors.
Kv4 channels underlie the main dendritic A-type Kv currents in hippocampal neurons and play a critical role in regulating the extent to which back-propagating action potentials invade the dendritic tree.
HERG channels exhibit functional properties different from other K channels; they are widely expressed in the brain where they contribute to setting the frequency and the discharge stability of neurons, adapting their intrinsic properties to signal processing and modulate the excitability of dopaminergic and GABAergic neurons
The KCa channels are highly conserved across species, and widely expressed in the human brain, they are made of two genetically well-distinct groups; the large conductance (BKca; KCa1.1), and the small/intermediate-conductance (SK/IK; KCa2.1, KCa2.2, KCa2.3, KCa3.1) KCa channels. With regard to gating mechanism, the Ca2+ sensitivity of SK/IK channels is provided by tightly bound calmodulin in neurons. KCa channels are widely distributed in the axons plasma membrane and at the presynaptic terminals and often located close to voltage-gated Ca2+ channels.
The calcium Ca2+ influx that follows neuronal excitation activates KCa channels whose outward K+ flux contributes to terminate the action potential and establish the after hyperpolarization (AHP) that closes Cav channels. This negative feedback control has been generally assumed to make KCa channels critical players in opposing repetitive firing and hyperexcitability.
KCa1.1 channels expression predominates in axons and pre-synaptic terminals of excitatory neurons located in cortex and hippocampus. The KCa1.1 channel activity is limited by the duration of the action potential-evoked Ca2+ transients, and consequently restricted to the action potential repolarization phase and the fast portion of the after-hyperpolarization (fAHP) and generally assumed to reduce neuronal excitability.
Members of the inwardly-rectifying family of K channels (Kir) are found in virtually every cell type where they are major regulators of K+ fluxes across membranes. Kir2.1 channels are highly expressed in brain, particularly in hippocampus, caudate, putamen, nucleus accumbens, and to lower levels in habenula and amygdala.
Several neurotransmitters, including dopamine, opioid, somatostatin, acetylcholine, serotonin, adenosine, and GABA exert their actions by modulating the activity of G protein-coupled Kir channels (GIRK) belonging to the subfamily 3 (Kir3).
K channels are recently implicated in many neurological diseases; epilepsy is one of these diseases. Many types of K channels are implicated including Kv and Kca channels.
Loss of Kv1.1 results in increased excitability in the CA3 recurrent axon collateral system, perhaps contributing to the limbic and tonic–clonic components of the observed epileptic phenotype of EA1. While Kv1.2 knockout mice display increased seizure susceptibility.
Variations in Kv4.2-containing channels in dentate granule cell and CA1 dendrites represent important mechanisms of the permanent epileptic phenotype in animal model of human temporal lobe epilepsy (TLE) and attractive therapeutic targets. Moreover, studies highlighted the essential nature of Kv4.2 in regulating the seizure susceptibility associated with epileptogenesis.
Kv7 channels inhibit neuronal excitability. Thus, mutations in Kv7 channels that are associated with Benign Familial Neonatal Convulsions (BFNC) are likely to be epileptogenic. Kv7.2, Kv7.3 and Kv7.5 expression is abundant in the hippocampus and cortex, areas of the brain known to be involved in idiopathic epilepsies as well as some types of acquired epilepsies. Also Mutations in Kv8.2 (KCNV2) results in epilepsy with an epileptic encephalopathy and with severe refractory epilepsy.
KCa1.1 channel have been clearly associated to epilepsy, convulsions was completely inhibited by the KCa1.1 channel blocker iberiotoxin (IbTX). Data suggest that both a loss-of-function of KCaβ3b-containing KCa1.1 channels and a gain-of-function of KCaβ1, KCaβ2, or KCaβ4-containing KCa1.1 channels would favor the epileptic phenotype.
It has been proposed that up-regulation of Kir2.1 in DGCs would counterbalance the hyper-excitability observed in TLE, thus functioning as an anti-convulsant. Ablation of the gene encoding for Kir3.2 channels (GIRK2) results in spontaneous convulsions and increased susceptibility for generalized seizures in rodents. Kir3 channel inhibition, induced by intrathecal administration of tertiapin, is pro-convulsant. Changes in Kir3 channel activity or availability throughout the brain may result in pro-convulsant or anti-convulsant effects.
There are many types of auxiliary subunit that modulates the activity of the associated K channel in distinct ways and implicated in channelepsy including Kvβ, KvLGI1 and KvKCHIP1.
Mutations in K channel genes contribute to inherited pain syndromes. Indeed, peripheral application of K channel openers on the cell body or terminals invariably decreases DRG excitability, whereas K channel blockers augment firing.
Several neurological disorders linked to peripheral hyperexcitability and pain of a neuropathic nature, such as neuromyotonia (NMT) or Morvan’s and cramp fasciculation syndromes, may be caused by erroneous Kv function due to host production of autoantibodies. Kv complex autoimmunity is an exciting development that may explain idiosyncratic pain in the absence of injury (e.g., fibromyalgia) or other presently enigmatic congenital pain states.
Diminished Kv1.2 activity contributes to mechanical and cold neuropathic pain by depolarizing the RMP, reducing threshold current, and augmenting firing rates in myelinated neurons but Kv4.2 can strongly modulate pain plasticity in dorsal horn neurons; thus Kv4.2-null mice exhibit quicker mechanical pain resolution following nerve injury
BKCA deletion enhances inflammatory pain without affecting acute or neuropathic behaviours .On the other hand SKCA and IKCA subunits in small neurons appear unaltered, suggesting that opening these channels may be a viable approach for chronic pain relief .SKCA are detected in a mixture of human and rodent DRGs, and may also contribute to pain phenotypes
Two pore potassium channels K2P have emerged as promising candidates for pain modulation owing to their cell type-specific expression and lower inter-family sequence identity.While KATP opening in the CNS is linked to the antinociception produced by systemic treatment with morphine, NSAIDs, or even gabapentin.
A dominant-negative mutation in the KCNK18 gene (TRESK) channel was linked to migraine with aura in a large pedigree. Mutant TRESK may increase the gain of the neuronal circuit underlying migraine headache and the identification of multiple frameshift and missense KCNK18 mutations in migraine patients implicates a role of TRESK channels in migraine pathophysiology by affecting the normal function of neurons in the migraine circuit. These results support a potential causal relationship between the frameshift TRESK mutation and migraine susceptibility.
In cerebrovascular stroke activation of potassium channels results in membrane hyperpolarization thereby decreasing neuronal activity and cell death under pathophysiological conditions. K2P channels play a major role in critical conditions leading to cerebral ischemia. These data were confirmed by the neuroprotective effect of several K2P2.1channel activators. Genetic depletion of K2P3.1 resulted in increased infarct volumes following transient or permanent MCAO.
Data provide compelling evidence that hypoxia depolarizes central neurons by specific inhibition of TASK1. Since this hypoxic depolarization may be an early, contributory factor in the response of central neurons to hypoxic/ischemic episodes. TASK1 channels largely serve a neuroprotective function in cerebral ischemia.
BKca activated by membrane depolarization and intracellular Ca2+ ions. Activity of KCa2 and KCa3.1 channels play an important role in vascular dynamics in cerebral ischemia. These channels play a key neuroprotective role during and after brain ischemia profoundly limiting brain damage and promoting survival.
Kv channels participate in cellular and molecular signaling pathways that regulate the life and death of neurons. Injury-mediated increased K+ efflux through Kv2.1 channels promotes neuronal apoptosis, contributing to widespread neuronal loss in cerebrovascular stroke. Furthermore, changes in K channel activity after subarachnoid hemorrhage may contribute to vascular insufficiency.
Autoimmune processes in MS up-regulate Kv1.3 when fully activated. Also anti-KIR4.1 antibodies with human complement into the cisterna magna of mice showed loss of KIR4.1 expression and activation of complement. In human KIR4.1 is a target of the autoantibody response in about 50% of persons with MS .A recent study found serum antibodies to KIR4.1 in the majority of children with ADD .These findings suggest that KIR4.1 is an important target of autoantibodies in childhood these data suggest that the antibodies to the non-myelin antigen KIR4.1 may be a biomarker for and contribute to the pathogenesis of MS.
Recent studies on potassium channel gene expression in the basal ganglia indicate that dysfunctions of various potassium channels may be involved in the pathogenesis of Parkinson’s disease. Results indicate that Kir2 channels may serve as a potential biomarker for screening. Increasing reports also suggest that KATP channels might be involved in the pathogenesis of PD and the blockade of neuronal KATP channels may contribute to neuroprotective effects in these patients. Also modulation of SKCa2 channels in dopaminergic neurons regulates neuronal excitability, survival, and neurotransmitter release, making them suitable candidates for therapeutic intervention in pathological conditions related to dopaminergic dysfunction, such as Parkinson’s disease.
KCa3.1 channels are present in microglia, which are activated by aggregated forms of Aβ and suppression of KCa3.1 might be useful for reducing microglia activity in Alzheimer’s disease. Genetic studies suggest that up-regulation of Kv3.4 and dysregulation of Kv3.1 alter potassium currents in neurons and leads to altered synaptic activity that may underlie the neurodegeneration observed in AD. Kv3.1 mRNA and protein levels were significantly low suggesting that a decrease in Kv3 currents could play a role in the cognitive symptom s of Alzheimer‘s disease and the anti-inflammatory and neuroprotective effects of KCa3.1 blockade would be suitable for treating AD.
Antibodies to VGKCs were considered characteristic of non paraneoplastic limbic encephalitis, neuromyotonia, and Morvan syndrome. The spectrum of neurologic manifestations and neoplasms associated VGKC autoimmunity is broader than previously recognized so evaluation for VGKC antibodies is recommended in the comprehensive autoimmune serologic testing of subacute idiopathic neurologic disorders
LGI1 is the autoantigen associated with limbic encephalitis previously attributed to voltage-gated potassium channels. The term limbic encephalitis associated with antibodies against voltage-gated potassium channels should be changed to limbic encephalitis associated with LGI1 antibodies, and this disorder should be classed as an autoimmune synaptic encephalopathy
Mutations in Kir2.6 in multiple Thyrotoxic hypokalemic periodic paralysis (TPP) patients may cause predisposition for the episodic weakness seen only during thyrotoxicosis. Alterations in the expression, subcellular localization, and/or kinetics of non-mutated potassium channels, which reduce outward potassium currents, have been implicated in the development of hypokalemia as well as pathological depolarization in periodic paralysis
Episodic ataxia type 1 is caused by mutations in the KCNA1 gene encoding Kv1.1 channel. At least six different mutations in the Kv1.1 channel have been identified in EA1. Kv1.1 channel dysfunction results in repetitive discharges in myelinated nerves. This mechanism underlies the neuromyotonic/myokymic discharges and susceptibility to seizures.
Spinocerebellar ataxia 13 (SCA13) is caused by mutations in the KCNC3 gene encoding Kv3.3 channel. Mutations in KCNC3 are presumed to suppress Kv3.3 currents in dominant-negative manner. Restoring Kv3.3 channels exclusively in Purkinje cells rescued the abnormalities in Purkinje neuron firing and motor coordination
The present findings confirmed that SK3 overexpression is a hallmark in Myotonic dystrophy type 1 muscle tissues. Increased expression of SK3 has a role in causing the symptoms of myotonia, because muscle injection of the highly specific SK inhibitor – apamin- reduced the electrical activity associated with myotonia. Over-expression in DM1 might be related to a differentiation defect SK3 might, therefore, play a key role in DM1 pathogenesis, more than being a mere downstream target of disordered myocytes.
Down regulation of the K channel is observed feature in injured nerve fibers also A-type and delayed rectifier K+ current in DRG down regulated in animals after spinal nerve ligation. This suppression is one of the major causative factors underlying peripheral sensitization of afferent nociceptive fibers and one of the major factors of persistent pain.
In the last years drugs that acts on K channels are approved and others still in the pipe. Retigabine is an anti-epileptic drug which is enhancing the activity of Kv7 channels in central nervous system resulting in reduction of neuronal excitability. Retigabine has recently been approved as adjunctive therapy in adults with partial-onset seizures.
Another drug is ICA-27243 which considered as a second-generation structure to retigabine, is a selective activator of Kv7.2/7.3. It showed in vivo animal tests a broad spectrum of anticonvulsant activity.
Meclofenamic acid and diclofenac have been described to also act as openers of Kv7 channels and to show robust antiepileptic properties.
4-Aminopyridine inhibits in dose-dependent manner fast Kv. It was approved for patients with MS to improve their walking .It also efficient in episodic ataxia type II.
BMS-204352 is KCa1.1 activator which entered clinical trials for stroke. It activates KCa1.1 channels and enters the brain quickly and reaches roughly 10-fold higher concentrations in the brain than in plasma. In permanent MCAO, an animal model of stroke, BMS-204352 reduced infarct areas measured at 24 hours in both normotensive and hypertensive rats but these results can’t be approved in human.