Voltage‐gated potassium channels and the diversity of electrical signalling

Jan, Yuh Nung

doi:10.1113/jphysiol.2011.224212

Cited by 212 publications

(149 citation statements)

References 65 publications

(98 reference statements)

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“…54 Voltage-gated potassium channels are located on axons and axon terminals 55 and serve to dampen neuronal excitability through the regulation of action potentials and the firing potentials of neurons. 56 Interestingly, the shaker locus in drosophila that exhibit motoric behaviors was found to encode a potassium channel. 57 Engineered Kcna1-null mice suffer from episodic eye blinking, increased startle response, hippocampal hyperexcitability and seizures.…”

Section: Hypo-hydroxymethylated Peaks (394 Peaks)mentioning

confidence: 99%

Genome-wide DNA hydroxymethylation identifies potassium channels in the nucleus accumbens as discriminators of methamphetamine addiction and abstinence

et al. 2016

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Epigenetic consequences of exposure to psychostimulants are substantial but the relationship of these changes to compulsive drug taking and abstinence is not clear. Here, we used a paradigm that helped to segregate rats that reduce or stop their methamphetamine (METH) intake (nonaddicted) from those that continue to take the drug compulsively (addicted) in the presence of footshocks. We used that model to investigate potential alterations in global DNA hydroxymethylation in the nucleus accumbens (NAc) because neuroplastic changes in the NAc may participate in the development and maintenance of drug-taking behaviors. We found that METH-addicted rats did indeed show differential DNA hydroxymethylation in comparison with both control and nonaddicted rats. Nonaddicted rats also showed differences from control rats. Differential DNA hydroxymethylation observed in addicted rats occurred mostly at intergenic sites located on long and short interspersed elements. Interestingly, differentially hydroxymethylated regions in genes encoding voltage (Kv1.1, Kv1.2, Kvb1 and Kv2.2)-and calcium (Kcnma1, Kcnn1 and Kcnn2)-gated potassium channels observed in the NAc of nonaddicted rats were accompanied by increased mRNA levels of these potassium channels when compared with mRNA expression in METH-addicted rats. These observations indicate that changes in differentially hydroxymethylated regions and increased expression of specific potassium channels in the NAc may promote abstinence from drug-taking behaviors. Thus, activation of specific subclasses of voltage-and/or calcium-gated potassium channels may provide an important approach to the beneficial treatment for METH addiction.

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Section: Hypo-hydroxymethylated Peaks (394 Peaks)mentioning

confidence: 99%

Genome-wide DNA hydroxymethylation identifies potassium channels in the nucleus accumbens as discriminators of methamphetamine addiction and abstinence

et al. 2016

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“…Tuning membrane conductances to achieve Type I behavior can be made easier if a neuron expresses many kinds of ion channels that all contribute to g s . It therefore seems more than a coincidence that there is an abundance of subtypes of A-type channels in many, if not most, nervous system genomes (51)(52)(53).…”

Section: Ion Channels Have Paradoxical Effects On Excitability In Difmentioning

confidence: 99%

Ion channel degeneracy enables robust and tunable neuronal firing rates

Drion

O’Leary

Marder

2015

Proc. Natl. Acad. Sci. U.S.A.

132

165

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Firing rate is an important means of encoding information in the nervous system. To reliably encode a wide range of signals, neurons need to achieve a broad range of firing frequencies and to move smoothly between low and high firing rates. This can be achieved with specific ionic currents, such as A-type potassium currents, which can linearize the frequency-input current curve. By applying recently developed mathematical tools to a number of biophysical neuron models, we show how currents that are classically thought to permit low firing rates can paradoxically cause a jump to a high minimum firing rate when expressed at higher levels. Consequently, achieving and maintaining a low firing rate is surprisingly difficult and fragile in a biological context. This difficulty can be overcome via interactions between multiple currents, implying a need for ion channel degeneracy in the tuning of neuronal properties.FI curve | bifurcation | Type I excitability | Type II excitability | reduced neuron model F iring rates encode the intensities of many signals in the nervous system, whether these are inputs from sensory organs, internal representations of percepts, or muscle contraction commands in motor nerves. For a neuron to represent continuously varying signals in its firing rate, it must be able to fire at low, high, and all intermediate frequencies. Experimentally, this means the frequency-input current (or FI) curve has a specific shape, called Type I, such that firing frequency smoothly approaches zero at current threshold (1-6). By contrast, so-called Type II neurons have a lower bound in their firing frequency and move abruptly from quiescence to fast spiking, with this transition visible as a sharp jump in the FI curve at threshold (1,3,5).Type I behavior is physiologically unlikely with a minimal set of membrane currents such as the voltage-gated sodium and delayed-rectifier potassium currents in the standard squid giant axon Hodgkin-Huxley model, which is Type II. Classic experimental (1, 7) and theoretical studies (3-5, 8, 9) revealed that a Type II membrane (such as a squid giant axon) can be turned into a Type I membrane by adding an inactivating (A-type) potassium conductance, I A . As the density of I A channels increases from zero, the membrane is able to support progressively lower firing frequencies at spiking threshold. The resulting linearization of the FI curve from Type II to Type I has clear consequences for encoding information in firing rate as well as other computational properties such as thresholding and gain scaling, all of which are subjects of intense research (10-17).We now show that this picture is incomplete. Using rigorous but intuitive methods (18) and building on previous technical results (19-21), we show that introducing I A to a Type II neuron progressively linearizes but then delinearizes the FI curve as I A density increases further. Consequently, I A density must be tuned in a strict range to achieve Type I behavior. However, we show that other, unrelated currents including v...

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“…9 The K v 1 or shaker subfamily channels comprise heterotetramers or homotetramers of a-subunits that have 6 a-helical transmembrane domains (S1-S6). 10 The transmembrane domains form the voltage sensor (S1-S4) and the surface of the channel pore (S5 and S6). The K v 1 family channels are broadly expressed; however, individual isoforms are expressed in different combinations in different tissues.…”

mentioning

confidence: 99%

DominantKCNA2mutation causes episodic ataxia and pharmacoresponsive epilepsy

Corbett

Bellows

et al. 2016

Neurology

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Objective: To identify the genetic basis of a family segregating episodic ataxia, infantile seizures, and heterogeneous epilepsies and to study the phenotypic spectrum of KCNA2 mutations.Methods: A family with 7 affected individuals over 3 generations underwent detailed phenotyping. Whole genome sequencing was performed on a mildly affected grandmother and her grandson with epileptic encephalopathy (EE). Segregating variants were filtered and prioritized based on functional annotations. The effects of the mutation on channel function were analyzed in vitro by voltage clamp assay and in silico by molecular modeling. KCNA2 was sequenced in 35 probands with heterogeneous phenotypes.Results: The 7 family members had episodic ataxia (5), self-limited infantile seizures (5), evolving to genetic generalized epilepsy (4), focal seizures (2), and EE (1). They had a segregating novel mutation in the shaker type voltage-gated potassium channel KCNA2 (CCDS_827.1: c.765_773del; p.255_257del). A rare missense SCN2A (rs200884216) variant was also found in 2 affected siblings and their unaffected mother. The p.255_257del mutation caused dominant negative loss of channel function. Molecular modeling predicted repositioning of critical arginine residues in the voltage-sensing domain. KCNA2 sequencing revealed 1 de novo mutation (CCDS_827.1: c.890G.A; p.Arg297Gln) in a girl with EE, ataxia, and tremor.Conclusions: A KCNA2 mutation caused dominantly inherited episodic ataxia, mild infantile-onset seizures, and later generalized and focal epilepsies in the setting of normal intellect. This observation expands the KCNA2 phenotypic spectrum from EE often associated with chronic ataxia, reflecting the marked variation in severity observed in many ion channel disorders. Neurology ® 2016;87:1975-1984 GLOSSARY EA 5 episodic ataxia; EE 5 epileptic encephalopathy; GATK 5 genome analysis toolkit; GGE 5 genetic generalized epilepsies; GTCS 5 generalized tonic-clonic seizures; ICCA 5 infantile convulsions choreoathetosis syndrome; RMS 5 root mean square.De novo mutations of KCNA2 have recently been reported in infantile-onset epileptic encephalopathies (EEs) in which infants present with uncontrolled seizures, developmental slowing or regression, and frequent epileptiform activity on EEG.1-6 Inherited mutations have not been described. KCNA2 has not been implicated in common pharmacoresponsive epilepsies such as the genetic generalized epilepsies (GGE), nor has an association with paroxysmal movement disorders been established.Paroxysmal neurologic disorders are often due to disorders of ion channel function. The episodic ataxias (EAs) are usually dominantly inherited and associated with a range of ion channel *These authors contributed equally to this work.

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Voltage‐gated potassium channels and the diversity of electrical signalling

Cited by 212 publications

References 65 publications

Genome-wide DNA hydroxymethylation identifies potassium channels in the nucleus accumbens as discriminators of methamphetamine addiction and abstinence

Genome-wide DNA hydroxymethylation identifies potassium channels in the nucleus accumbens as discriminators of methamphetamine addiction and abstinence

Ion channel degeneracy enables robust and tunable neuronal firing rates

DominantKCNA2mutation causes episodic ataxia and pharmacoresponsive epilepsy

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