Kv Channels Research Articles

Blockade of Voltage-Gated K+ Channels in Rabbit Coronary Arterial Smooth Muscle Cells by the Antipsychotic Drug Zotepine.

Zotepine is a second-generation antipsychotic that demonstrates significant efficacy in antagonizing D2 and 5-HT2A receptors. Although clinical investigations have shown that administering zotepine is associated with an increased prevalence of hyperglycemia and a heightened risk of cardiovascular disease, the side effects of zotepine on voltage-gated K+ (Kv) channels have not been established. Zotepine suppressed the vascular Kv channels in rabbit coronary arterial smooth muscle cells in a concentration-dependent manner, with an IC50 of 5.3 ± 0.4 μM and a Hill coefficient of 1.6 ± 0.2. The decay rate of inactivation was significantly accelerated by zotepine. Applying zotepine (10 μM) shifted the steady-state inactivation curve in a negative direction. Applying train pulses at 1 and 2 Hz resulted in a progressive increase in blockage of the Kv currents by zotepine. Furthermore, zotepine prolonged the recovery time from inactivation. Although pretreatment with the Kv2.1 subtype inhibitor stromatoxin-1 and the Kv7 subtype inhibitor linopirdine did not change the degree of zotepine-induced inhibition of Kv currents, pretreatment with the Kv1.5 channel inhibitor DPO-1 decreased the inhibitory effects of zotepine on Kv currents. Zotepine also induced membrane depolarization. These results indicate that zotepine inhibits Kv currents (mainly Kv1.5 subtype) in dose-, time-, and use (state)-dependent manners by changing the steady-state inactivation curve.

A functional unbalance of TRPM8 and Kv1 channels underlies orofacial cold allodynia induced by peripheral nerve damage

A functional unbalance of TRPM8 and Kv1 channels underlies orofacial cold allodynia induced by peripheral nerve damage

Kv4 channels improve the temporal processing of auditory neurons in the cochlear nucleus.

Kv4 channels generate A-type current known to regulate neuronal excitability. Its role in processing timing information is understudied, especially in the auditory system where temporal information is crucial for hearing. In the cochlear nucleus, principal bushy neurons are specialized for temporal processing with distinct biophysical properties owing to their expression of various voltage-gated ion channels. Previous studies reported conflicting information regarding the expression and potential role of Kv4 channels in these neurons. We explored these questions using electrophysiology in CBA/CaJ mice of either sex. A-type current was isolated from 88% of bushy neurons using Kv4 channel-selective blocker Jingzhaotoxin-X (JZ-X), which increased the intrinsic excitability of bushy neurons without altering their synaptic input. During high-rate activity, JZ-X treatment significantly increased the spike jitter and reduced the firing threshold of bushy neurons. In old mice, A-type current in bushy neurons reduced in magnitude but maintained current density, accompanied by decreased membrane surface area. In contrast, TEA-sensitive Kv3 current reduced in both magnitude and current density, indicative of a greater contribution to the altered biophysical properties of bushy neurons during ageing. Our findings suggest that Kv4 channels play significant roles in regulating neuronal excitability and improving the temporal processing of bushy neurons. Such function is likely retained with age and is not the primary mechanism driving compromised temporal processing under age-related hearing loss. KEY POINTS: Most bushy neurons of the cochlear nucleus exhibit Kv4-mediated A-type current. A-type current regulates neuronal excitability of bushy neurons without contributing to the synaptic transmission at the endbulb of Held. A-type current increases the firing threshold and improves the temporal precision of spikes in bushy neurons during high-rate activity. A-type current reduces peak amplitude in bushy neurons during ageing but maintains current density. Decreased Kv3 current, rather than Kv4 current, likely play more significant roles in altering the biophysical properties of bushy neurons during ageing, contributing to compromised temporal processing during age-related hearing loss.

The potassium channel subunit KV1.8 (Kcna10) is essential for the distinctive outwardly rectifying conductances of type I and II vestibular hair cells

In amniotes, head motions and tilt are detected by two types of vestibular hair cells (HCs) with strikingly different morphology and physiology. Mature type I HCs express a large and very unusual potassium conductance, gK,L, which activates negative to resting potential, confers very negative resting potentials and low input resistances, and enhances an unusual non-quantal transmission from type I cells onto their calyceal afferent terminals. Following clues pointing to KV1.8 (Kcna10) in the Shaker K channel family as a candidate gK,L subunit, we compared whole-cell voltage-dependent currents from utricular HCs of KV1.8-null mice and littermate controls. We found that KV1.8 is necessary not just for gK,L but also for fast-inactivating and delayed rectifier currents in type II HCs, which activate positive to resting potential. The distinct properties of the three KV1.8-dependent conductances may reflect different mixing with other KV subunits that are reported to be differentially expressed in type I and II HCs. In KV1.8-null HCs of both types, residual outwardly rectifying conductances include KV7 (Knq) channels. Current clamp records show that in both HC types, KV1.8-dependent conductances increase the speed and damping of voltage responses. Features that speed up vestibular receptor potentials and non-quantal afferent transmission may have helped stabilize locomotion as tetrapods moved from water to land.

The potassium channel subunit KV1.8 (Kcna10) is essential for the distinctive outwardly rectifying conductances of type I and II vestibular hair cells.

In amniotes, head motions and tilt are detected by two types of vestibular hair cells (HCs) with strikingly different morphology and physiology. Mature type I HCs express a large and very unusual potassium conductance, gK,L, which activates negative to resting potential, confers very negative resting potentials and low input resistances, and enhances an unusual non-quantal transmission from type I cells onto their calyceal afferent terminals. Following clues pointing to KV1.8 (Kcna10) in the Shaker K channel family as a candidate gK,L subunit, we compared whole-cell voltage-dependent currents from utricular HCs of KV1.8-null mice and littermate controls. We found that KV1.8 is necessary not just for gK,L but also for fast-inactivating and delayed rectifier currents in type II HCs, which activate positive to resting potential. The distinct properties of the three KV1.8-dependent conductances may reflect different mixing with other KV subunits that are reported to be differentially expressed in type I and II HCs. In KV1.8-null HCs of both types, residual outwardly rectifying conductances include KV7 (Knq) channels. Current clamp records show that in both HC types, KV1.8-dependent conductances increase the speed and damping of voltage responses. Features that speed up vestibular receptor potentials and non-quantal afferent transmission may have helped stabilize locomotion as tetrapods moved from water to land.

Perillyl Alcohol Promotes Relaxation in Human Umbilical Artery.

Perillyl alcohol (POH) is a monoterpenoid found in plant essential oils and has been shown to relax murine vessels, but its effect on human vessels remains poorly studied. The study aimed to characterize the effect of POH on human umbilical arteries (HUA). Rings of HUA were obtained from uncomplicated patients and suspended in an organ bath for isometric recording. The vasorelaxant effect of POH in HUA was evaluated on basal tone and electromechanical or pharmacomechanical contractions, and possible mechanisms of action were also investigated. POH (1-1000 μM) altered the basal tone of HUA and completely relaxed HUA rings precontracted with KCl (60 mM) or 5-HT (10 μM), obtaining greater potency in the pharmacomechanical pathway (EC50 110.1 μM), suggesting a complex interference in the mobilization of extra- and intracellular Ca2+. POH (1000 μM) inhibited contractions induced by BaCl2 (0.1-30 mM) in a similar way to nifedipine (10 μM), indicating a possible blockade of L-type VOCC. In the presence of potassium channel blockers, tetraethylammonium (1 mM), 4-aminopyridine (1 mM), or glibenclamide (10 μM), an increase in the EC50 value of the POH was observed, suggesting a modulation of the activity of BKCa, KV, and KATP channels. The data from this study suggest that POH modulates Ca2+ and K+ ion channels to induce a relaxant response in HUA.

Constitutive opening of the Kv7.2 pore activation gate causes KCNQ2-developmental encephalopathy

Pathogenic variants in KCNQ2 encoding Kv7.2 voltage-gated potassium channel subunits cause developmental encephalopathies (KCNQ2-encephalopathies), both with and without epilepsy. We herein describe the clinical, in vitro, and in silico features of two encephalopathy-causing variants (A317T, L318V) in Kv7.2 affecting two consecutive residues in the S6 activation gate that undergoes large structural rearrangements during pore opening; the disease-causing A356T variant in KCNQ3, paralogous to the A317T variant in KCNQ2, was also investigated. Currents through KCNQ2 mutant channels displayed increased density, hyperpolarizing shifts in activation gating, faster activation and slower deactivation kinetics, and resistance to changes in the cellular concentrations of phosphatidylinositol 4,5-bisphosphate (PIP2), a critical regulator of Kv7 channel function; all these features are consistent with a strong gain-of-function effect. An increase in the probability of single-channel opening, with no change in membrane abundance or single-channel conductance, was responsible for the observed gain-of-function effects. All-atom molecular dynamics simulations revealed that the mutations widened the inner pore gate and stabilized a constitutively open channel configuration in the closed state, with minimal effects on the open conformation. Thus, mutation-induced stabilization of the inner pore gate open configuration is a molecular pathogenetic mechanism for KCNQ2-related encephalopathies.

GABA Receptors and Kv7 Channels as Targets for GABAergic Regulation of Acetylcholine Release in Frog Neuromuscular Junction.

Effects of gamma-aminobutyric acid (GABA) and some selective GABAergic ligands on the quantal acetylcholine (ACh) release in the frog neuromuscular contacts were investigated using combination of microelectrode technique with fluorescent and immunohistochemical assays. Significant attenuation of ACh release was observed in the presence of GABA as well as selective GABAA and GABAB receptor agonists. Neither GABAA nor GABAB antagonists abolished to full extent this effect of GABA. Fluorescent assay allowed to detect the GABA-induced opening of K+ channels, which was inhibited by XE-991, a selective antagonist of Kv7 type. Electrophysiological recordings of endplate potentials in the presence of XE-991 confirmed the contribution of Kv7 type potassium channels to the effects of GABA on ACh release that was not associated with GABAA and GABAB receptors activation. Note that XE-991 effectively precluded the action of retigabine, neuronal Kv7 channel opener, on ACh release. Immunohistochemical assay revealed that frog mature skeletal muscle fibers contain a significant amount of GABA, and substantial amount of GABA can be released in the extracellular space at the muscle contractions induced by prolonged high-frequency nerve stimulation. Besides, some binding sites for exogenous GABA were detected on the plasma membranes. It is concluded that GABA, in addition to affecting GABAA and GABAB receptors, can directly activate Kv7 channels, thereby negatively modulating the evoked ACh release. Endogenous GABA may serve as a retrograde regulator of neurotransmitter exocytosis.

Kv3.3 Expression Enhanced by a Novel Variant in the Kozak Sequence of KCNC3.

Pathogenic variants in KCNC3, which encodes the voltage-gated potassium channel Kv3.3, are associated with spinocerebellar ataxia type 13. SCA13 is a neurodegenerative disease characterized by ataxia, dysarthria and oculomotor dysfunction, often in combination with other signs and symptoms such as cognitive impairment. Known disease-causing variants are localized in the protein coding regions and predominantly in the transmembrane and voltage sensing domains. In a patient with an ataxic movement disorder and progressive cognitive decline, the c.-6C>A variant was detected in the Kozak sequence of KCNC3. The Kozak sequence is responsible for efficient initiation of translation. Functional analysis of the new c.-6C>A variant and the upstream 5'-UTR region of KCNC3 by luciferase assays, quantitative PCR and methylation analysis shows increased protein expression but no effect on transcription rate. Therefore, increased translation initiation of KCNC3 transcripts compared to wild-type Kozak sequence seems to be the cause of the increased expression. Variants in the regulatory elements of disease-causing genes probably play an underestimated role.

Isoleucine gate blocks K+ conduction in C-type inactivation.

Many voltage-gated potassium (Kv) channels display a time-dependent phenomenon called C-type inactivation, whereby prolonged activation by voltage leads to the inhibition of ionic conduction, a process that involves a conformational change at the selectivity filter toward a non-conductive state. Recently, a high-resolution structure of a strongly inactivated triple-mutant channel kv1.2-kv2.1-3m revealed a novel conformation of the selectivity filter that is dilated at its outer end, distinct from the well-characterized conductive state. While the experimental structure was interpreted as the elusive non-conductive state, our molecular dynamics simulations and electrophysiological measurements show that the dilated filter of kv1.2-kv2.1-3m is conductive and, as such, cannot completely account for the inactivation of the channel observed in the structural experiments. The simulation shows that an additional conformational change, implicating isoleucine residues at position 398 along the pore lining segment S6, is required to effectively block ion conduction. The I398 residues from the four subunits act as a state-dependent hydrophobic gate located immediately beneath the selectivity filter. By mutating I398 to Asparagine, ion permeation can be resumed in the kv1.2-kv2.1-3m channel, which was not a reversion C-type inactivation, since AgTxII fails to block the ionic permeation of kv1.2-kv2.1-3m_I398N. As a critical piece of the C-type inactivation machinery, this structural feature is the potential target of a broad class of QA blockers and negatively charged activators thus opening new research directions towards the development of drugs that specifically modulate gating-states of Kv channels.

Potassium ion channel modulation at cancer-neural interface enhances neuronal excitability in epileptogenic glioblastoma multiforme.

The central nervous system (CNS) is increasingly recognized as a critical modulator in the oncogenesis of glioblastoma multiforme (GBM), with interactions between cancer and local neuronal circuits frequently leading to epilepsy; however, the relative contributions of these factors remain unclear. Here, we report a coordinated intratumor shift among distinct cancer subtypes within progenitor-like families of epileptic GBM patients, revealing an accumulation of oligodendrocyte progenitor (OPC)-like subpopulations at the cancer-neuron interface along with heightened electrical signaling activity in the surrounding neuronal networks. The OPC-like cells associated with epilepsy express KCND2, which encodes the voltage-gated K+ channel KV4.2, enhancing neuronal excitability via accumulation of extracellular K+, as demonstrated in patient-derived exvivo slices, xenografting models, and engineering organoids. Together, we uncovered the essential local circuitry, cellular components, and molecular mechanisms facilitating cancer-neuron interaction at peritumor borders. KCND2 plays a crucial role in mediating nervous system-cancer electrical communication, suggesting potential targets for intervention.

Mechanism of selectivity filter constriction in potassium channel: Insights from high-throughput steered molecular dynamics simulations

Potassium channels are essential for regulating cellular excitability by controlling K+ ion flow. In voltage-gated potassium (Kv) channels, C-type inactivation modulates action potentials and holds significant physiological and clinical importance. The selectivity filter (SF) of potassium channels functions as the C-type inactivation gate by alternating between conductive and non-conductive states. The bacterial KcsA potassium channel, characterized by well-defined structural features, serves as an ideal model for investigating this mechanism through molecular dynamics (MD) simulations. However, limitations in computational power and the time scales of C-type inactivation, which extend up to seconds, have constrained a comprehensive understanding of this process. This study used high-throughput steered molecular dynamics (SMD) simulations, employing a knowledge-based acceleration strategy, to capture spontaneous SF constriction within nanoseconds in KcsA. Over a thousand SMD simulations recorded hundreds of SF constriction events, revealing a common constriction mechanism driven by an ion occupancy switch from state 13 to state 14 within the SF, facilitated by water molecules located behind the SF. Simulations of the E71V-mutated KcsA suggest that this constricted state and mechanism may also extend to Kv-like channels, albeit with reduced water dependence. These findings underscore the essential roles of ions and water molecules in regulating protein dynamics and highlight strategies for high-throughput MD studies to further explore protein dynamics.

Molecular mapping of KCNE4-dependent regulation of Kv1.3.

The voltage-gated potassium channel Kv1.3 plays a crucial role in the immune system response. In leukocytes, the channel is coexpressed with the dominant negative regulatory subunit KCNE4, which associates with Kv1.3 to trigger intracellular retention and accelerating C-type inactivation of the channel. Previous research has demonstrated that the main association between these proteins occurs through both C-termini. However, these data fail to fully elucidate the KCNE4-dependent modulation of channel kinetics. In the present study, we analyzed the contribution of each KCNE4 domain to the modulation of Kv1.3. Our results further confirmed that the C-terminus of KCNE4 is the main determinant involved in the association-triggered intracellular retention of the channel. Moreover, interactions throughout the transmembrane region were also observed. Both the C-terminus and, especially, the transmembrane domain of KCNE4 accentuated the C-type inactivation of Kv1.3. Our data provide, for the first time, the molecular effects that a KCNE peptide, such as KCNE4, exerts on a Shaker channel, such as Kv1.3. Our results pave the way for understanding the molecular mechanisms underlying potassium channel modulation and suggest that KCNE4 participates in the conformational rearrangement of the Kv1.3 architecture, altering the C-type inactivation of the channel.

KCNB1-Leptin receptor complexes couple electric and endocrine function in the melanocortin neurons of the hypothalamus.

The neurons of the melanocortin system regulate feeding and energy homeostasis through a combination of electrical and endocrine mechanisms. However, the molecular basis for this functional heterogeneity is poorly understood. Here, a voltage-gated potassium (Kv+) channel named KCNB1 (alias Kv2.1) forms stable complexes with the leptin receptor (LepR) in a subset of hypothalamic neurons including proopiomelanocortin (POMC) expressing neurons of the Arcuate nucleus (ARHPOMC). Mice lacking functional KCNB1 channels (NULL mice) have less adipose tissue and circulating leptin than WT animals and are insensitive to anorexic stimuli induced by leptin administration. NULL mice produce aberrant amounts of POMC at any developmental stage. Canonical LepR-STAT3 signaling-which underlies POMC production-is impaired, whereas non-canonical insulin receptor substrate PI3K/Akt/FOXO1 and ERK signaling are constitutively upregulated in NULL hypothalami. The levels of proto-oncogene c-Fos-that provides an indirect measure of neuronal activity-are higher in arcuate NULL neurons compared to WT and most importantly do not increase in the former upon leptin stimulation. Hence, a Kv channel provides a molecular link between neuronal excitability and endocrine function in hypothalamic neurons.

Neuroprotection by 4R-cembranoid against Gulf War Illness-related Chemicals is mediated by ERK, PI3K, and CaMKII pathways

Gulf War Illness (GWI) has been consistently linked to exposure to pyridostigmine (PB), N,N-Diethyl-meta-toluamide (DEET), permethrin (PER), and traces of sarin. In this study, diisopropylfluorophosphate (DFP, sarin surrogate) and the GWI-related chemicals were found to reduce the number of functionally active neurons in rat hippocampal slices. These findings confirm a link between GWI neurotoxicants and N-Methyl-D-Aspartate (NMDA)-mediated excitotoxicity, which was successfully reversed by Edelfosine (a phospholipase Cβ (PLCβ3) inhibitor) and Flupirtine (a Kv7 channel agonist).To test whether 4R-cembranoid (4R), a nicotinic α7 acetylcholinesterase receptor (α7AChR) modulator known for its neuroprotective properties, can restore hippocampal neurons from glutamate-induced neurotoxicity, we exposed rat hippocampal slices with DFP for 10 min followed by 60 min treatment with 4R. We investigated the 4R mechanisms of neuroprotection after preincubation with LY294002, PD98059, and KN-62. The inhibition of the phosphatidylinositol 3-kinase (PI3K), mitogen-activated protein kinase (MEK1/2), and calcium/calmodulin-dependent protein kinase (CaMKII) abrogated the protective effect of 4R against DFP-induced neurotoxicity. In separate experiments, after incubation with DFP, followed by 4R for 1 h, cellular extracts were prepared for Western blotting of phospho-Akt, phospho-GSK3β, phosphorylated extracellular signal-regulated kinase (ERK)1/2, CaMKII and cAMP response element-binding protein (CREB). Our results show that DFP induces neuronal dysfunction by dephosphorylation, while 4R restores the phosphorylation of Akt, GSK3, ERK1/2, CREB, and CaMKII. Moreover, our proteomics analysis supported the notion that 4R activates additional signaling pathways related to enhancing neuronal signaling, synaptic plasticity, and apoptotic inhibition to promote cell survival against DFP, offering biomarkers for developing treatment against GWI.

A novel loss-of-function KCNB1 gene variant in a twin with global developmental delay and seizures.

Human voltage-gated potassium (Kv) channels are expressed by a 40-member gene family that is essential for normal electrical activity and is closely linked to various excitability disorders. Function-altering sequence variants in the KCNB1 gene, which encodes the neuronally expressed Kv2.1 channel, are associated with neurodevelopmental disorders including developmental delay with or without epileptic activity. In this study, we describe a 40-month-old fraternal twin who presented with severe neurodevelopmental delay. Electroencephalogram recordings at 19 months of age revealed poor sleep architecture and the presence of multifocal epileptiform discharges. The individual's fraternal twin was neurotypical, and there was no family history of neurodevelopmental delay or seizures. Whole genome sequencing at 33 months of age for the proband revealed a de novo variant in KCNB1 [c.1154C > T/p.Pro385Leu], encoding a proline-to-leucine substitution at residue 385, in the extracellular region immediately preceding Kv2.1 transmembrane segment 6 (S6). Cellular electrophysiological analysis of the effects of the gene variant in heterologously expressed Kv2.1 demonstrated that homozygous Kv2.1-P385L channels were completely non-functional. Channels generated by a 50/50 expression of wild-type Kv2.1 and Kv2.1-P385L, designed to mimic the proband's heterozygous status, revealed a partially dominant-negative effect, resulting in an 81% reduction in current magnitude. The dramatic loss of function in Kv2.1 is the most likely cause of the severe developmental delay and seizure activity in the proband, further enriching our phenotypic understanding of KCNB1 developmental encephalopathies.

Discovery of a potent, Kv7.3-selective potassium channel opener from a Polynesian traditional botanical anticonvulsant

Plants remain an important source of biologically active small molecules with high therapeutic potential. The voltage-gated potassium (Kv) channel formed by Kv7.2/3 (KCNQ2/3) heteromers is a major target for anticonvulsant drug development. Here, we screened 1444 extracts primarily from plants collected in California and the US Virgin Islands, for their ability to activate Kv7.2/3 but not inhibit Kv1.3, to select against tannic acid being the active component. We validated the 7 strongest hits, identified Thespesia populnea (miro, milo, portia tree) as the most promising, then discovered its primary active metabolite to be gentisic acid (GA). GA highly potently activated Kv7.2/3 (EC50, 2.8 nM). GA is, uniquely to our knowledge, 100% selective for Kv7.3 versus other Kv7 homomers; it requires S5 residue Kv7.3-W265 for Kv7.2/3 activation, and it ameliorates pentylenetetrazole-induced seizures in mice. Structure-activity studies revealed that the FDA-approved vasoprotective drug calcium dobesilate, a GA analog, is a previously unrecognized Kv7.2/3 channel opener. Also an active aspirin metabolite, GA provides a molecular rationale for the use of T. populnea as an anticonvulsant in Polynesian indigenous medicine and presents novel pharmacological prospects for potent, isoform-selective, therapeutic Kv7 channel activation.

Alzheimer's disease induced neurons bearing PSEN1 mutations exhibit reduced excitability.

Alzheimer's disease (AD) is a devastating neurodegenerative condition that affects memory and cognition, characterized by neuronal loss and currently lacking a cure. Mutations in PSEN1 (Presenilin 1) are among the most common causes of early-onset familial AD (fAD). While changes in neuronal excitability are believed to be early indicators of AD progression, the link between PSEN1 mutations and neuronal excitability remains to be fully elucidated. This study examined iPSC-derived neurons (iNs) from fAD patients with PSEN1 mutations S290C or A246E, alongside CRISPR-corrected isogenic cell lines, to investigate early changes in excitability. Electrophysiological profiling revealed reduced excitability in both PSEN1 mutant iNs compared to their isogenic controls. Neurons bearing S290C and A246E mutations exhibited divergent passive membrane properties compared to isogenic controls, suggesting distinct effects of PSEN1 mutations on neuronal excitability. Additionally, both PSEN1 backgrounds exhibited higher current density of voltage-gated potassium (Kv) channels relative to their isogenic iNs, while displaying comparable voltage-gated sodium (Nav) channel current density. This suggests that the Nav/Kv imbalance contributes to impaired neuronal firing in fAD iNs. Deciphering these early cellular and molecular changes in AD is crucial for understanding disease pathogenesis.

Voltage-gated potassium channels and genetic epilepsy.

Recent advances in exome and targeted sequencing have significantly improved the aetiological diagnosis of epilepsy, revealing an increasing number of epilepsy-related pathogenic genes. As a result, the diagnosis and treatment of epilepsy have become more accessible and more traceable. Voltage-gated potassium channels (Kv) regulate electrical excitability in neuron systems. Mutate Kv channels have been implicated in epilepsy as demonstrated in case reports and researches using gene-knockout mouse models. Both gain and loss-of-function of Kv channels lead to epilepsy with similar phenotypes through different mechanisms, bringing new challenges to the diagnosis and treatment of epilepsy. Research on genetic epilepsy is progressing rapidly, with several drug candidates targeting mutated genes or channels emerging. This article provides a brief overview of the symptoms and pathogenesis of epilepsy associated with voltage-gated potassium ion channels dysfunction and highlights recent progress in treatments. Here, we reviewed case reports of gene mutations related to epilepsy in recent years and summarized the proportion of Kv genes. Our focus is on the progress in precise treatments for specific voltage-gated potassium channel genes linked to epilepsy, including KCNA1, KCNA2, KCNB1, KCNC1, KCND2, KCNQ2, KCNQ3, KCNH1, and KCNH5.

A novel KCNC3 gene variant in the voltage-dependent Kv3.3 channel in an atypical form of SCA13 with dominant central vertigo.

Potassium channel mutations play an important role in neurological diseases, such as spinocerebellar ataxia (SCA). SCA is a heterogeneous autosomal-dominant neurodegenerative disorder with multiple sub-entities, such as SCA13, which is characterized by mutations in the voltage-gated potassium channel Kv3.3 (KCNC3). In this study, we present a rare and atypical case of SCA13 with a predominant episodic central rotational vertigo, while the patient suffered only from mild progressive cerebellar symptoms, such as dysarthria, ataxia of gait and stand, and recently a cognitive impairment. In this patient, we identified a heterozygous variant in KCNC3 (c.2023G > A, p.Glu675Lys) by next-generation sequencing. This Kv3.3E675K variant was studied using voltage-clamp recordings in Xenopus oocytes. While typical SCA13 variants are dominant-negative, show shifts in the voltage-dependence of activation or an altered TBK1 regulation, the Kv3.3E675K variant caused only a reduction in current amplitude and a more pronounced cumulative inactivation. Thus, the differences to phenotypes observed in patients with classical SCA13 mutations may be related to the mechanism of the observed Kv3.3 loss-of-function. Treatment of our patient with riluzole, a drug that is known to also activate potassium channels, turned out to be partly beneficial. Strikingly, we found that the Kv3.3 and Kv3.3E675K inactivation and the frequency-dependent cumulative inactivation was antagonized by increased extracellular potassium levels. Thus, and most importantly, carefully elevated plasma potassium levels in the physiological range, or novel drugs attenuating Kv3.3 inactivation might provide novel therapeutic approaches to rescue potassium currents of SCA13 variants per se. In addition, our findings broaden the phenotypic spectrum of Kv3.3 variants, expanding it to atypical phenotypes of Kv3.3-associated neurological disorders.