But among all ion channels, the key regulators of neuronal excitability are the voltage-gated potassium channels (K_V), the largest family of K⁺ channels (Shah and Aizenman, 2014). These K_V channels are divided into 12 subfamilies, named as K_V1–K_V12. They are composed of 4 α-subunits, each one containing 6 α-helical transmembrane domains (S1–S6), voltage sensor (S1–S4) and the ion pore (S5–S6). The N- and C-terminals are intracellular and they have different regulation sites. They differ in biophysical and pharmacological properties and in auxiliary β-subunits too, that modulate their activity, trafficking and location (Kuang et al., 2015). Although some channels regulate neuronal excitability, others participate also in the duration of cardiac action potentials and are involved in cell proliferation or even cancer (Bachmann et al., 2020).

Voltage-gated potassium channels are transmembrane channels responsible for returning the depolarized cell to a resting state after an action potential (Gazulla and Berciano, 2023). Therefore, K_V channels are important modulating neuronal excitability in the CNS, but also participate regulating other organs function.

Changes in ion physical function or gaining or depletion of channel function results in channelopathies, several of them associated to neurodegenerative disorders (Orfali et al., 2024). In this review, we will describe the role of some voltage-gated potassium channel in age related neurodegenerative disorders and their modulation for these diseases therapy.

During Alzheimer disease (AD), the amyloid β-peptide (Aβ) deposition causes synaptic dysfunction and consequently neuronal loss. There have been identified several K_V channels that can regulate the firing rate (K_V1, K_V4 or K_V7) or the duration of the action potential (K_V2 or K_V3) (Li, 2022) (Figure 1). Moreover, the impairment in these K_V channels is associated with several pathogenic mechanisms. For instance, K_V3.4 expression increase due to Aβ deposition initiates apoptotic processes and K_V2.1 contributes to potassium mobilization during neuronal apoptosis, so overexpression of this channel promotes this process (Sun et al., 2022). The formation of K_V2.1 oligomers by oxidative agents contribute to neurotoxicity and this phenomenon is aggravated in AD models (Cotella et al., 2012; Wei et al., 2018). This oligomerization triggers integrin signaling, activating Src tyrosine kinases via autophosphorylated FAK (Yu et al., 2019).

Meanwhile, enhanced K_V1.3 expression in microglia, a key regulator of microglia function and related to inflammatory response, after amyloid plaque formation produces proinflammatory cytokine release and apoptotic cascade (reviewed in Revuelta et al., 2022). K_V1.5 is mostly studied in the heart, but it is also presented in the brain and its activity is associated with apoptosis. It has been seen that H₂O₂ increases channel activity (Caouette et al., 2003). In contrast, CO inhibits K_V1.5 current by the increase of ROS, which directly regulates the channel. Besides, the increase of NO in response to CO inhibits the channel activity by channel phosphorylation (Al-Owais et al., 2017).

Concerning K_V4 channelopathies they have been linked to AD, schizophrenia and epilepsy (Cercós et al., 2021). Particularly in AD, the expression of KChIP3 (K_V channel-interacting protein 3 or calsenilin) is increased. This KChIP3 mechanically promote the translocation of K_V4 channels to cell membrane, modulating the pacemaker activity (Buxbaum, 2004; Wu et al., 2023). They are associated with presenilins (PS1 and PS2), transmembrane proteins that are related to early-onset familial AD (Bähring, 2018) KChIP3 also modifies the gating of the channel, delaying the kinetic inactivation and accelerates the kinetic recovery from inactivation. Indeed, K_V4.3 is involved in transient outward A type potassium current in neurons (Lopez-Hurtado et al., 2019).

The proapoptotic protein pentraxin (NP1) is another protein presented in dystrophic neurites in AD and related to the regulation of synapse density (Ma et al., 2018). This NP1 regulates the surface expression of K_V7.2, a channel that controls neuronal excitability. K_V7 channels generate M-current, slow voltage dependent outward current that contributes to the maintenance of the resting membrane potential, but can also exert a dampening effect on neuronal excitability. K_V7.2 overexpression prevents cells from increased neuronal excitability and synapse, a situation provoked by NP1 downregulation during AD (Figueiro-Silva et al., 2015) (Table 1).

The neuropathological characteristics of Parkinson’s disease (PD) (Figure 1) are the degeneration of dopaminergic neurons in the CNS and the presence of Lewy bodies, α-synuclein-(SNCA)-positive intracytoplasmic inclusions (Poewe et al., 2017). Moreover, in PD pathophysiology there is inflammation due to microgliosis and astrogliosis and it seems that this inflammation is crucial for PD progression (Table 1) (Tansey and Goldberg, 2010).

It has been described that K_V1.3 expression is upregulated in some animal models of PD, in vitro experiments, and postmortem human PD brains. Fyn, the Src family kinase that is involved in the microglia activation (Panicker et al., 2015), could regulate the K_V1.3 channel expression both transcriptionally and post-translationally modifying its activity and therefore increasing neuroinflammation (Sarkar et al., 2020).

A-type K⁺ current, generated by K_V4.3 and KChip3 interaction, is present in CNS DAergic neurons that contribute to regulating the neuron’s tonic activity (Chen et al., 2018). A53T-SNCA mice mutant which overexpress human α-synuclein with a PD-associated mutation (A53T), showed a oxidative dysfunction of this current induced by the overexpression of the α-synuclein, increasing the firing rate frequency of the dopaminergic substantia nigra neurons (Subramaniam et al., 2014); in both PD animal models and PD patients K_V4.3 expression changes have been observed.

K_V7 channels are expressed in GABAergic and Dopaminergic neurons in the striatum. Activation of K_V7 channels induces hyperpolarization of Dopaminergic neurons and inhibits the excitatory activity (Hansen et al., 2006). Four out of five (K_V7.2–K_V7.5) M-channels members’ activity is regulated by oxidative and nitrosylation processes in sensory neurons. While oxidation by H₂O₂ augmented channel activity (Linley et al., 2012), nitrosylation by NO donors inhibited it (Ooi et al., 2013). In oxidative-stress-induced neurodegeneration model, oxidation of the S2–S3 linker of the K_V7 enhance the M-current, protecting cells due to neuronal silencing (Gamper et al., 2006; Nuñez et al., 2023).

During PD there is a progressive loss of dopamine (DA) in substantia nigra and consequently in the striatum. Recent studies have proposed the therapeutic role of KCNQ channel blockers as they increase the neuronal bursting pattern in the substantia nigra and enhance DA synthesis in the striatum (Liu et al., 2018).

ERG or Kv11 K⁺ channels are present in the locus coeruleus (LC) of the brain. This area is related to cognition, learning and memory, among other roles (Uematsu et al., 2017; James et al., 2021; Dahl et al., 2022). This channel prevents increased firing rate and discharge irregularities in those LC neurons (Hasan et al., 2022). In PD, the LC neurons degeneration is present before DAergic neurons degeneration. It has been seen that in Parkinsonian rats the use of ERG K⁺ channels blockers improves the locomotor deficits, whereas the activators do the opposite, increase burst mode and impaired motor function (Huang et al., 2017). So, this channel dysfunction could be implicated in PD.

Huntington disease (HD) is a progressive neurodegenerative disease caused by the CAG triples expansion in the Huntington gene (MacDonald et al., 1993). Neurons from striatum and the cerebral cortex are the two main regions affected during HD. Particularly in the medium size spiny neurons (MSNs) from the striatum, K⁺ channels are necessary to maintain the membrane potential hyperpolarized and the slow firing rate. During HD there is a reduction of K_V2.1 channel in MSNs disrupting synaptic integration and consequently information processing (Zhang et al., 2018). At the same time, it is also reported a reduction of M-current, reducing the control of the excitability in striatal output neurons of R6/2 mice (Figure 2). Retigabine, a potential antiepileptic drug, not only restores the hyperactivity network, but also improves motor skills of these mice (Cao et al., 2015).

Moreover, the previously mentioned KChIP3 is downregulated in HD patients and is associated with neuroprotection (An et al., 2000). Several K_V4.3/KChIP3 channel complex modulators have been proposed in the last years as therapeutic targets to modulate channel gating and promote neuroprotection during HD (Lopez-Hurtado et al., 2019).

Spinocerebellar ataxia (SCA) is an autosomal dominant neurodegenerative disorder characterized by progressive ataxia with variable symptoms. There are more than 40 distinct genetic SCA (Bhandari et al., 2024). In humans, K_V channelopathies are linked to disorders in cell excitability, but only few are the principal responsible for neurodegeneration, mostly the ones that produce spinocerebellar ataxias (SCA) (Zhang and Kaczmarek, 2016). In 2002 there was identified a mutation in the KCND3 gene, that codifies K_V4.3 channel that causes SCA19 (Verbeek et al., 2002). Mutations in this gene provoke impairments in the channel traffic from the endoplasmic reticulum to Golgi membrane, reducing the functionality of the channel and consequently provoking the disorder (Duarri et al., 2012; Zanni et al., 2021).

In the mouse model of SCA3, altered K_V channel function is associated with Purkinje neuron dysfunction; specifically, the inactivation of K_V3 current seems to be the cause (Shakkottai et al., 2011).

The SCA13 is another disorder produced by a mutation in the gene that encodes K_V3.3 channel resulting in cerebellar neurodegeneration. The major function of this channel is to drive the repolarization phase of action potential, so mutations in this gene produce disorders of excitability and consequently cerebellar neurodegeneration (Rudy and McBain, 2001; Zhang and Kaczmarek, 2016).

Another K_V channel that has been linked to episodic ataxia type 1 (EA1) is the KCNA1 (K_V1.1) (Tan et al., 2013). A mutation in KCNA1 gene is the only responsible for the EA1 resulting in episodic ataxia and myokymia. Mutations in this gene can modify the channel current density and consequently channel gating, provoking dysfunctions in the circuits located in several tissues, such as cerebellum, hippocampus or cortex in EA (D’Adamo et al., 2020).

Although certain Na_V-blocking anticonvulsant drugs (carbamazepine, phenytoin, and lamotrigine) are used to reduce seizures, they do not work as therapy. In this sense, K_V1 (K_V1.1 and K_V1.3) channelopathies are involved in cell excitability and firing rates in diverse pathological processes, small molecule research and in silico approaches are currently being studied to find modulators of these channels as a target (D’Adamo et al., 2020). K_V1.1 dysfunction, for instance, is responsible for episodic ataxia type 1 (EA1). In that regard, some negative modulators of K_V1.1 have been found (Wacker et al., 2012), but no molecule able to specifically modulate K_V1.1 channels has yet been described. Experimental studies have demonstrated that some resin acids generated by some plants (piramic acid and dehydroabietic acid) are able to open K_V channels in vitro by changing voltage-dependent activation towards negative potentials (Ottosson et al., 2015).

Further, hyperactivation of the mTOR pathway is involved in the increased expression and altered distribution of K_V1.1 channels in the hippocampus of mice with cortical dysplasia with epilepsy. In those mice, the classical mTOR inhibitor rapamycin normalized the levels of K_V1.1, thus proposing that the mTOR pathway may be another possible research target to modulate K_V1.1 expression (Nguyen and Anderson, 2018).

On the other hand, the K_V1.3 channel is considered a novel therapeutic target to treat neuroinflammatory disorders, such as PD and AD, as it plays a crucial role in microglial cells subsets (Wang et al., 2020). During these neurological disorders, there is an overexpression of K_V1.3 channels concluding that K_V1.3 specific blockers could mitigate neuroinflammation, and become specific therapeutic candidates during AD or PD (reviewed in Revuelta et al., 2022).

Some studies showed that PAP-1, a K_V1.3 blocker, could reduce cerebral Aβ load, diminish neuroinflammation, enhance plasticity of hippocampal neurons and improve behavioral deficits in APP/PS1 transgenic mice (Maezawa et al., 2018). Furthermore, PAP-1 administration reduced neurodegeneration and neuroinflammation in animal models of PD (Sarkar et al., 2020). Moreover, it has been shown that some toxins produced by certain animals can act as a modulator of K_V1.3 channels. Specifically, the effects of BmKTX, a scorpion toxin, targeting K_V1.3 have been studied as a possible treatment of AD and PD, as it could block microglial activation and thus reduce the neuroinflammation (Wang et al., 2020).

K_V2.1 channel overexpression promotes neurotoxicity and neuronal apoptosis in AD models (Sun et al., 2022), whereas in HD there is a reduction in these channels in medium-sized spiny neurons (MSNs) contributing a synaptic disruption (Zhang et al., 2018).

It has been described that tacrine, a cholinesterase inhibitor, can act on K_V channels. It reduces the expression of K_V2.1 channels and increases cell proliferation providing neuroprotection during AD (Hu et al., 2020). AD-related mutations can promote increased ROS production leading to K_V2.1 channel function loss. Therefore, inhibition of this channel could offer a novel therapeutic approach for AD (Frazzini et al., 2016).

Indeed, several studies relate the activation of K_V2.1 channel activators with a better prognosis during HD, since these channels are downregulated in the disease and are associated with the mitochondrial oxidative stress generated in HD (Zhang et al., 2018).

K_V3.3 channel dysfunction result in the SCA13. A recent study shows that the genetic suppression of K_V3.3 channels using antisense oligonucleotides (ASOs) can reverse the SCA13 outcomes (Zhang et al., 2021), meaning that targeting K_V3.3 expression may provide a potential therapeutic approach for SCA13.

Concerning the K_V3.4 channel, its expression is upregulated during AD due to Aβ deposition, initiating neuronal apoptosis. Recent results suggest that rapid activation/inactivation of these channels could be involved in Aβ-induced neurotoxicity. Therefore, reducing the expression and/or function of K_V3.4 in brains with AD could protect Aβ-mediated synaptic alterations (Yeap et al., 2022). Among K_V3.4 targets, the BDS-I (blood depressing substance-I), a marine toxin extracted from Anemonia Sulcate, inhibits the channel activity, provoking a reduction of neuronal apoptosis, reducing the expression of certain stress markers, such as active caspase 12; preventing Aβ1-42 induced reactive oxygen species (ROS) production and decreasing the release of pro-inflammatory cytokines (Piccialli et al., 2021).

In the hippocampus, K_V4 channelopathies are related to epilepsy, schizophrenia, and AD. Therefore, pharmacological modulation of somato-dendritic subthreshold-activating K⁺ current could function as a therapeutic target for these pathologies (Cercós et al., 2021).

Besides, as previously mentioned, KChIP3 is downregulated in HD patients, promoting neuroprotection. Hence, K_V4.3/KChIP3 channel complex inhibitors have been proposed as potential therapeutic targets to promote neuroprotection during HD (Lopez-Hurtado et al., 2019). To date, some molecules, such as repaglidine and CL-888, have been shown to bind and inhibit K_V4.3 currents.

In addition to their well-known relation with infantile epileptic encephalopathies, K_V7 channelopathies are also linked to several age related neurodegenerative diseases (including AD and PD), such as neurotoxicity and alteration of GABAergic and Dopaminergic neuron activation properties. Downregulation of K_V7.2 provokes neurotoxicity in AD and therefore, finding activators of these channels could be a therapeutic approach to increase neuronal excitation and synapse. Among other drugs, retigabine, has been described as capable of increasing potassium K_V7.2–7.3 channel currents (Czuczwar et al., 2010). Retigabine acts as a positive allosteric modulator, stabilizing the open form of these channels after binding to a hydrophobic pocket near the channel gate (Gunthorpe et al., 2012). Nevertheless, this drug is not in use due to side effects. Even so, this suggests that pharmacological modulation of the M-current could exert beneficial effects on the cognitive deficits involved in the pathophysiology of neurological disorders (Alles and Smith, 2021).

On the other hand, upregulation of K_V7 channels causes a modulation of GABAergic and Dopaminergic neuron activation properties. In this sense, XE991 blocks KCNQ channels promoting action potential in DAergic neurons and increasing their excitability. Furthermore, XE991 enhances suprathreshold synaptic responses and promotes depolarization of striatal GABAergic projection neurons (Chen et al., 2018).

K_V11 or ERG channel could be another therapeutic target for PD since the modulation of subthalamic discharge by ERG channel inhibitors attenuates motor dysfunction in PD rats (Huang et al., 2017). The partial block of ERG K⁺ channels by antipsychotic drugs has also been linked to better dopaminergic neuronal excitability (Shepard et al., 2006).