Potassium Channels of the Airway Epithelium

ABSTRACT

Maintenance of potassium (K⁺) homeostasis across cell membranes is essential for life. While systemic K⁺ balance is primarily regulated by the kidneys and intestines, ion channels, pumps, and transporters govern K⁺ movement across epithelial barriers at the cellular level. Despite the prevalence of diseases caused by disrupted K⁺ homeostasis, the role of K⁺ channels in the lungs has received comparatively little attention. The airway epithelium expresses a diverse array of K⁺ channels that regulate key functions such as transepithelial ion transport, ciliary beating, and mucus secretion. These processes are fundamental components of mucociliary clearance (MCC), the primary innate defense mechanism of the lungs. Dysfunction of MCC is central to muco‐obstructive diseases, including cystic fibrosis (CF), chronic obstructive pulmonary disease (COPD), and asthma. While K⁺ channels were once considered therapeutic targets for enhancing anion secretion in CF, initial interest waned. However, it has been reinvigorated by recent findings showing that drugs targeting CFTR can also modulate airway epithelial K⁺ channels and facilitate MCC. In this review, we compile current evidence on targeting K⁺ channels to treat muco‐obstructive diseases. We discuss therapeutic opportunities offered by K⁺ channel modulators, highlight emerging functions of these channels in the airways, and outline priorities for future research.

Practioner Points.

• Potassium (K⁺) channels in the airway epithelium critically regulate mucociliary clearance by sustaining anion secretion, modulating Na⁺ absorption, and controlling ciliary beating and mucus release.

• Emerging evidence shows that certain CFTR correctors can modulate K⁺ channel functions, offering a promising complementary strategy to restore MCC in muco‐obstructive diseases such as cystic fibrosis (CF), COPD, and asthma.

• Future research must determine K⁺ channel expression across specific cell types of the airway epithelium, and assess their impact on the airway microbiome and viral responses, to fully harness their therapeutic potential.

1. Introduction

Potassium (K⁺) is the most abundant intracellular cation, concentrated within the cytoplasm by the Na⁺/K⁺‐ATPase, a critical step for the maintenance of the resting membrane potential. Consequently, fundamental cellular functions such as nerve conduction, muscle contraction, transepithelial transport, or inflammasome activation, among many others, depend on K⁺ fluxes energized by its electrochemical gradient generated by ATP hydrolysis.

Although 98% of total K⁺ in the body is maintained in the intracellular compartment, changes in plasma concentration are clinically relevant [1]. Therefore, circulating K⁺ levels are tightly regulated through a balance between dietary intake, shifts from the extracellular space to intracellular compartments in liver and muscle, and renal excretion [2]. The colon is the second most important organ for K⁺ excretion, responsible for nearly 8%–10% of the daily intake. Notably, colonic excretory capacity can increase significantly during renal insufficiency or acute K⁺ overload [3, 4].

While the critical roles of K⁺ channel functions in the kidney, pancreas, heart, and central nervous system are well‐established and such knowledge has led to successful therapies for arrhythmias, diabetes, and multiple sclerosis, their function in the airway epithelium remains poorly understood [5, 6, 7]. Early on, K⁺ channel activators were proposed as bronchodilators to reduce smooth muscle contraction, a life‐threatening symptom of asthma, but the airway epithelium was not considered as a target to reduce, for example, mucus secretion that greatly contributes to lower airway obstructions [8]. Up to date, a large number of K⁺ channels have been detected in the airway epithelium, but their exact functions have remained largely understudied, precluding the potential use of K⁺ channel modulators in diseases affecting the airways [9]. In this revision, we will focus on data that describes K⁺ channel functions in airway epithelium including new observations pointing toward their potential as therapeutic targets to treat human muco‐obstructive diseases.

1.1. The Mucociliary Clearance in Lung Health

Mucociliary clearance (MCC) is the primary defense system of the lungs. Inhaled particles become trapped in mucus within the airway surface liquid (ASL), preventing them from reaching the distal airways. Mucus is produced primarily by goblet cells in humans and club cells in mice. The periciliary liquid (PCL) is a thin fluid layer (~8 μm in height) maintained by a balance between chloride secretion and sodium absorption, critical for sustaining ciliary beating. Ciliated cells propel the ASL and mucus‐trapped particles toward the larynx to be swallowed or eliminated [10, 11, 12, 13]. The ASL also contains bicarbonate, essential for mucus maturation, and several other metabolites produced by epithelial and immune cells, and the airway microbiota whose composition becomes altered during lung disease [14, 15, 16, 17].

Other rare epithelial cell types (ionocytes, pulmonary neuroendocrine cells, and brush cells) represent ~1% of the epithelium. Ionocytes are proposed to fine‐tune ASL electrolyte composition [18]. Pulmonary neuroendocrine cells have the potential to regulate MCC by releasing neuromodulators that induce goblet cell hyperplasia and are associated with exacerbation of asthmatic symptoms [19], whereas brush cells trigger acute fluid secretion and mucus transport in response to bacterial molecules [20] (Figure 1). As will be detailed in the following sections, K⁺ channels play a central role in regulating many of the cellular functions underlying MCC.

FIGURE 1.

The function of epithelial airway cells in MCC. The coordinated and specific functions of different epithelial cells are the core of MCC. While Na⁺‐absorptive and Cl⁻secretory cells maintain adequate ASL volume, cilia from ciliated cells can properly expand and beat to move mucus (produced by goblet cells) and trapped particles out of the airways. Ionocytes participate in fine‐tuning of ASL composition including the secretion of bicarbonate (HCO₃ ⁻) that is essential for mucus maturation. Brush cells can secrete acetylcholine (ACh) and activate anion secretion in muscarinic receptor 3 (M3r) positive cells. The role of pulmonary neuroendocrine cells has not been determined yet. More details in Section 1.1. Cartoon generated using Biorender.

2. K⁺ Channels as Modulators of Airway Epithelial Functions

Located in either apical or basolateral membranes, K⁺ channels maintain membrane potential and couple to other secretory and absorptive networks of ion channels and co‐transporters. As in other epithelial tissues, apical and basolateral K⁺ channels help maintain a hyperpolarized membrane potential, thereby enhancing the electrochemical driving force required for Cl⁻ and HCO₃ ⁻ secretion as well as Na⁺ absorption, in a coordinated process often referred to as ion channel crosstalk [21]. In addition, apical K⁺ channels directly contribute to secretion by facilitating K⁺ efflux into the lumen. Other functions that depend on K⁺ channels include the control of cilia beating frequency and the release of mucins by regulating cytoplasmic Ca²⁺ levels [22].

Even though mRNA expression studies have shown the presence of several tens of K⁺ channels transcripts in the airways of mice, rats, and humans [9], we will focus on the available functional data that highlights the physiological relevance of K⁺ channels function in airway homeostasis rather than function‐orphan gene expression (Figure 2).

FIGURE 2.

K⁺ channels in airway epithelial function. The models describe epithelial airway functions that conforms MCC. The green tick indicates a proven role and the red X indicates that the current evidence discard a role in the specific function. The “n.d.” indicates that the function has not been tested for a particular K⁺ channel. *Indicates that the K₂P channel activity was found in the apical rather than basolateral membrane. To simplify the models NKCC1 on the Cl⁻ secretion model was not included. Even though, the localization of KCa3.1 and K_ATP channels in the cilia has not been demonstrated, functional experiments demonstrate that they control ciliated cell function. A detailed explanation and discussion of the experimental evidences are included in Sections 2.1.2 to 2.1.4.3.

2.1. A Brief Historical Recollection of K⁺ Fluxes and Conductances in Mammalian Airway Epithelium

Airway fluid secretion occurs at all stages of life in mammals, including prenatally. Early evidence came from rabbit fetal trachea ligation and human congenital bronchial obstructions, which caused lung distension attributed to fluid secretion [23, 24, 25]. Subsequent analysis of fetal lung fluid using radiolabeled ions established airway K⁺ concentrations ranging from 6.3 to 57 mM [26, 27, 28].

Early electrophysiological recordings in adult rat tracheas showed that Na⁺ absorption and Cl⁻ secretion accounted for nearly 95% of the short‐circuit current, while unidirectional K⁺ fluxes were symmetrical, indicating passive transfer. This study also determined that K⁺ secretion was occurring almost exclusively in the alveolar epithelium [29]. Accordingly, K⁺ in fetal lamb alveolar fluid (5.06 ± 0.05 mM) was slightly higher than in plasma (4.78 ± 0.17 mM) [27]. In canine airways, distal regions had approximately 10 mEq·L⁻¹ more K⁺ than proximal regions, consistent with a K⁺ secretory component present only in distal airways [30, 31, 32]. Whether lower K⁺ levels in proximal airway reflects enhanced absorption, reduced secretion, or both remains unclear.

More recent studies using different methodological approaches have reported discrepant K⁺ concentrations in ASL. In healthy volunteers, bronchial ASL was found to contain K⁺ levels 3–4 times higher than in plasma, whereas in mice, ASL K⁺ concentration was similar to plasma [33, 34]. Using a ratiometric K⁺‐sensitive fluorescent indicator, measurements of K⁺ concentrations in the apical fluid of human bronchial epithelial cell (HBEC) monolayers yielded values of 17–35 mM [35]. In contrast, another study reported much lower values (approximately 3 mM) in HBECs monolayers using flame photometry [36]. These discrepancies likely reflect variations in sampling techniques, sample sources, and the technical challenges inherent in accurately measuring K⁺ concentrations in native tissues, leaving the true luminal K⁺ concentration unresolved. Moreover, the non‐gastric H⁺/K⁺ ATPase (ATP12A), which participates in K⁺ absorption in the airways, is not expressed across all species; its function therefore influences ASL K⁺ concentrations in a species‐specific manner [37, 38].

2.1.1. The KCa3.1 Calcium‐Activated K⁺ Channel of Intermediate Conductance

Patch‐clamp recordings in canine tracheal epithelia identified a basolateral Ca²⁺‐dependent K⁺ channel (unitary conductance: 19.4 pS) required for sustained Cl⁻ secretion [39]. This channel likely corresponds to KCa3.1 (IK‐1, KCNN4), as its unitary conductance in other species (9–35 pS mouse, 11–30 pS human) aligns with that of the native canine channel [40, 41]. In human bronchial 16HBE14o‐ cells and nasal epithelium, basolateral KCa3.1 supports Ca²⁺‐activated anion secretion, evidenced by using the KCa3.1 inhibitor clotrimazole [42, 43]. Even though clotrimazole effect was not reproduced in the mouse trachea [44], it was fully reproduced in the Kcnn4 ^−/− mouse [45]. This discrepancy may reflect reported off‐target effects of clotrimazole [46].

Primary human bronchial cells from healthy donors exhibit KCa3.1 currents, activated by 1‐EBIO and blocked by TRAM‐34, confirming earlier observations in cell lines and other species [47]. Subsequently, KCa3.1 was shown to sustain the electrochemical gradient for ENaC‐mediated Na⁺ absorption in HBECs, a finding corroborated in the Kcnn4 ^−/− mice. Moreover, Kcnn4 silencing induced an increase in ciliary beating frequency possibly by membrane hyperpolarization resulting from reduced Na⁺ entry, thereby increasing intracellular Ca²⁺ influx [45, 48]. Supporting their important role in basolateral recycling of K⁺, KCa3.1 protein expression was observed at the basolateral membrane in rat airway epithelium [49]. In summary, KCa3.1 channel supports Ca²⁺‐activated anion secretion, supports ENaC‐mediated Na⁺ absorption, and controls ciliary beating frequency (Figure 2).

2.1.2. The BK Channel

Apical BK channels facilitate K⁺ secretion, a role previously reviewed [50]. Nevertheless, new evidence has emerged since then. BK is a heteromultimer of pore‐forming α subunit KCNMA1 (SLO1), four β (KCNMB1‐4), and four γ subunits (LRRC26, 38, 52, 55) that regulate Ca²⁺ and voltage sensitivity, enabling functional diversity across tissues [51, 52].

Initial studies found no effect of the BK blocker iberiotoxin on mouse tracheal short‐circuit current or apical ⁸⁶Rb⁺ efflux in 16HBE14o‐ cells, ruling out BK roles in electrogenic or electroneutral K⁺ secretion [42, 44]. Later, HBEC monolayers revealed ATP‐evoked apical currents blocked by paxilline. BK blockade or silencing reduced cilia beating frequency, attributed to decreased ASL volume from reduced Cl⁻ secretion gradient [53]. Moreover, a subsequent study identified BK channels in the apical membrane of ciliated, but not secretory cells, though a direct role in ciliary regulation was not established [54].

The BK opener NS1619 inhibited neurogenic mucus secretion in ferret trachea, suggesting a role in goblet cell function. Although, the effect was attributed to neurons [55], later evidence showed that goblet cells display prominent BK channel activity [56]. Goblet cells from the intestine and the airways express the LRRC26 auxiliary subunit of BK channels, which shifts their activation toward negative membrane potentials, a property that enables like BK channel function in non‐excitable epithelial cells. Moreover, the genetic silencing of either Kcnma1 or Lrrc26 exacerbates inflammatory intestinal disease in the animal model, indicating that BK is a regulator of the epithelial inflammatory response [56, 57]. Glucocorticoids have shown to control the functional expression of BK and its splice variants in cultured HBECs, further indicating that the pharmacological modulation of BK activity impacts airway inflammation [54]. Finally, BK activity is influenced by splice variants like STREX that is inhibited by cAMP and variant ZERO that confers a cAMP‐dependent upregulation as shown in colon epithelium. In STREX expressing tissues, cAMP inhibits K⁺ secretion, synergizing with CFTR to sustain luminal electronegativity and paracellular fluid secretion [58, 59, 60]. In summary, when expressed with LRRC26 apical BK channels are the main facilitators of airway K⁺ secretion (Figure 2).

2.1.3. The cAMP‐Activated K⁺ Channel

The cAMP‐activated K⁺ channel is a heteromultimer of KCNQ1 (KvLQT1, Kv7.1) pore subunit and regulatory subunit KCNE3, a member of the voltage‐activated K⁺ channel family regulated by phosphorylation. KCNQ1 is highly expressed in mouse lung tissue [61] and in the human airway epithelium [62]. The selective inhibitor chromanol‐293B demonstrated that KCNQ1/KCNE3 is essential for cAMP‐dependent anion secretion in both species, and due to its dependence on cAMP, became a main focus in CF research [43, 44, 62, 63]. Chromanol 293 also indirectly reduced amiloride‐sensitive Na⁺ absorption in mouse trachea, indicating that basolateral KCNQ1/KCNE3 sustains the gradient for both anion secretion and Na⁺ absorption [44, 63]. Nevertheless, the Kcne3^−/− mouse model showed normal Na⁺ absorption, whereas the reduction in both cAMP‐ and Ca²⁺‐stimulated electrogenic anion secretion phenocopied chromanol 293B. Despite the impairment in anion transport, no evidence of mucus accumulation or inflammatory cell infiltration was observed in this mouse model. These findings suggest that alternative basolateral K⁺ channels, such as KCa3.1, may be sufficient to preserve normal MCC in murine airways following the loss of KCNQ1/KCNE3 activity [45, 64].

Comparatively, tracheal and colonic epithelia show tissue‐specific K⁺ channel roles. In mouse colon, Kcnn4 knockdown specifically impairs Ca²⁺‐activated anion secretion, whereas silencing Kcnq1 or Kcne3 affects only cAMP‐induced anion secretion. In contrast, in the mouse trachea, Kcnn4 knockdown again selectively blocks Ca²⁺‐activated anion secretion, but Kcne3 silencing disrupts both cAMP‐ and Ca²⁺‐activated pathways [45, 64, 65, 66, 67, 68]. Supporting this interconnection, chromanol 293B also inhibited Ca²⁺‐activated anion secretion in human nasal biopsies, indicating that Ca²⁺ agonists also can trigger cAMP‐dependent pathways that activate KCNQ1/KCNE3 and CFTR in the airway epithelium [43, 69].

Although KCNE3 blockade or silencing nearly abolishes cAMP‐activated anion secretion, the silencing of another subunit, Kcne1, increased both basal and cAMP‐activated anion currents [63]. This may reflect KCNQ1 release from KCNE1, allowing interaction with KCNE3 to form a constitutively open channel [70], or KCNE1 switching TMEM16A from Ca²⁺‐dependent to voltage‐dependent activation [71]. In summary, KCNQ1/KCNE3 is essential for Ca²⁺‐ and cAMP‐dependent anion secretion in the airways (Figure 2).

2.1.4. Other K⁺ Channels

In comparison with KCa3.1, BK, and KCNQ1/KCNE3, the study of other K⁺ channels in the airways has been relatively limited. In the following subsections we briefly summarize the principal findings concerning the protein expression and functional involvement of K₂P, K_ATP, and Kir7.1 in the airways (Figure 2).

2.1.4.1. Two‐Pore Domain K⁺ Channels (K₂P)

The use of inhibitors of K₂P channels bupivacaine and quinidine inhibited both amiloride‐sensitive Na⁺ absorption and cAMP‐induced anion secretion in HBECs monolayers indicating that K⁺ background currents regulate the potential of the apical membrane [72]. The same study determined protein expression of TWIK1 and TASK2 in the apical membrane and TWIK2 in the cilia. Finally, a different study postulated that TASK1 could participate in cilia beating control, but experiments in Task1 knock‐out mouse models and pharmacological blockade were inconclusive [73].

2.1.4.2. The K_ATP Channel Family

K_ATP channels integrate cellular metabolic states with membrane potential regulation, influencing epithelial functions. In the 16HBE14o‐airway epithelial cell line, Kir6.1, Kir6.2, and SUR1 subunits are functionally expressed in the basolateral membrane [74, 75]. In ciliated cells, K_ATP channel opening promotes Ca²⁺ influx and enhances ciliary beating, an effect blocked by glibenclamide [48].

2.1.4.3. The Kir7.1 Inward‐Rectifying K⁺ Channel

Genetically modified mouse models for Kir7.1 (encoded by Kcnj13) have revealed its expression spanning from the trachea to the bronchioles, in the basolateral membrane of a subset of epithelial cells in both adult and newborn mice [76, 77], and mouse models with impaired Kir7.1 function have shown severe abnormalities in mouse airway development [78, 79].

3. Epithelial K⁺ Channels in Muco‐Obstructive Airway Diseases

As we learned, K⁺ channels control diverse functions of airway epithelium; thus, alterations in their activity may contribute to disease by disrupting critical mechanisms involved in MCC. Conversely, targeting these channels could reduce signs and symptoms in diseases where epithelial dysfunction is a main player. Disturbance of mucus homeostasis can have different causes, like reduced fluid secretion or increased absorption that ultimately will reduce ASL volume, critically reducing the activity of the cilia and generating mucostasis. In many cases, the inflammatory response will increase mucus production and release that can progress to airway obstruction. Mucostasis is a hallmark of muco‐obstructive pulmonary diseases like cystic fibrosis (CF), chronic obstructive pulmonary disease (COPD), and asthma. Even though the etiology of each disease is different, the pathological mucus hyper‐secretion and accumulation, goblet cell hyperplasia, airway obstruction, unresolved inflammation, progressive bronchiectasis, and emphysema are present in most patients [80, 81]. In the next sections, we summarize and discuss the evidences of the involvement of K⁺ channels in muco‐obstructive disease and how its pharmacological modulation can improve MCC function.

3.1. Cystic Fibrosis

This genetic disease is caused by mutations in the CFTR anion channel that severely reduce MCC function due to decreased Cl⁻ and HCO₃ ⁻ secretion. The reduction of ASL volume and pH leads to mucus accumulation and small airway obstruction, driven by sustained epithelial inflammation [82]. This mucus stasis and impaired mucociliary clearance create a favorable environment for bacterial colonization, with chronic Pseudomonas aeruginosa infection as a direct consequence linked to lung function decline, increased hospitalizations, and reduced life expectancy. To break this noxious cycle, the main therapeutic focus is restoring CFTR secretory function to recover ASL volume, favoring mucus maturation and removal. Highly effective CFTR modulator therapy (HEMT), such as the triple combination ETI (elexacaftor/tezacaftor/ivacaftor), has dramatically improved quality of life and extended life expectancy for people with CF (pwCF) who have access to the therapies. However, around 10% of pwCF are ineligible or experience adverse reactions [83, 84, 85]. Accordingly, these therapeutic shortcomings underscore the need to pursue complementary therapeutic strategies, including revisiting previously proposed scientific hypotheses.

Before the advent of new therapies, substantial interest focused in activate alternative anion channels to bypass the CFTR defect, particularly after identifying TMEM16A as a Ca²⁺‐activated anion channel in human airway epithelium [86]. Early stidies also proposed that activating K⁺ channels could enhance the efficacy of both CFTR and alternative anion channels [43, 87]. Indeed, activation of KCa3.1 and KCNQ1/KCNE3 channels in CF nasal and bronchial epithelium was shown to potentiate secretion, however this hypothesis remained largely unexplored for decades [43, 88]. More recently, the dual effects of KCa3.1 inhibition on airway epithelial ion transport have revealed a more complex pharmacological profile. In one hand, is hypothesized that VX‐445‐mediated inhibition of KCa3.1 may contribute to the adverse effects observed in patients receiving HEMPT, presumably through reduced chloride secretion [89]. On the other hand, KCa3.1 inhibition also limits ENaC‐mediated Na⁺ absorption in airway epithelium, an effect that enhances mucociliary clearance by preserving airway surface liquid volume [45]. This ENaC‐modulating property aligns with the mechanism of action of inhaled ENaC blockers, such as ETD001, which are currently under clinical investigation for muco‐obstructive diseases [90]. While the net balance of these opposing effects in vivo remains to be determined, the potential benefit of KCa3.1 inhibition on Na⁺ absorption should not be overlooked. Further studies are warranted to dissect the relative contributions of these pathways and to clarify whether KCa3.1 inhibition offers a therapeutic advantage in the context of CF and other airway diseases.

Recently, the concept of enhancing BK activity to augment fluid secretion has resurfaced. However, while evidence for apical BK is abundant, evidence for basolateral BK activity in airway epithelium remains lacking [91]. For example, the anti‐hypertensive drug losartan restores the expression of the LRRC26 subunit, which is downregulated in nasal epithelium of pwCF, improving MCC function and reducing inflammation [92]. More recently, VX‐659 (bamocaftor), VX‐445 (elexacaftor), VX‐121 (vanzacaftor), and the enantiomer R‐vanzacaftor have shown to produce sustained BK activation [93, 94]. These findings suggest BK channels as regulators of MCC and support BK potentiation as a therapeutic strategy for pwCF patients ineligible for HEMT. But given the exceptionally large unitary conductance of BK (130–300 pS) [95] compared to CFTR (7–8 pS) [96, 97], widespread co‐expression of both channels at the apical membrane of the same airway epithelial cells appears physiologically unlikely. A mathematical model of secretory epithelium predicted that, to maximize Cl⁻ secretion, the apical K⁺ conductance should not exceed ~17% of total K⁺ conductance; otherwise, Cl⁻ secretion declines [98]. Theoretically, if all CFTR‐expressing cells also contained apical BK, the resulting K⁺ efflux would partially dissipate the lumen‐negative transepithelial potential difference. This would reduce the paracellular driving force for Na⁺ and fluid secretion, compromising ASL volume. Thus, BK‐positive cells likely represent a minority population relative to CFTR‐positive cells, and any co‐expressing subpopulation is probably limited. Such cellular segregation would allow BK‐mediated K⁺ secretion to support localized anion and fluid transport without compromising epithelial ion balance. This concept is consistent with observations in other secretory epithelia, such as the submandibular gland, where CFTR and BK channels are differentially distributed across specialized cell types: BK is expressed in submandibular acinar cells and in ductal ionocytes whereas CFTR is predominantly expressed in submandibular ductal cells [99, 100, 101, 102, 103].

Despite their therapeutic promise, the clinical application of BK channel agonists or blockers warrants cautious evaluation due to the central role of BK channels in neurological functions, where their deregulation is implicated in several human diseases [104]. A parallel concern arises in the pulmonary context, where the activation of K⁺ secretion through BK channels in human bronchial epithelial (HBEC) monolayers has been shown to increase the attachment of Pseudomonas aeruginosa , promote bacterial aggregation, and enhance biofilm formation. The causal role of BK channels in this process was confirmed when these pathogenic effects were prevented by paxilline, a selective BK blocker. The underlying mechanism reveals that Pseudomonas aeruginosa exhibits chemotaxis toward K⁺ ions, utilizing the high‐affinity K⁺ transporter KdpFABC and the K⁺ sensing system KdpDE. Notably, silencing this operon significantly reduced biofilm growth. The clinical relevance of this finding is underscored by the fact that this operon is highly conserved in Pseudomonas aeruginosa isolates from patients with CF [105].

3.1.1. Cystic Fibrosis Related Diabetes (CFRD)

High glucose directly inhibits airway K⁺ channels by reducing K_ATP and KCNQ1/KCNE3 conductance which delays epithelial repair [106], and by decreasing apical BK currents via LRRC26 downregulation, which further reduces ASL volume in CF‐HBECs monolayers [107]. The reported effects of airway hyperglicaemia on K⁺ channels' activity might cooperate to the accelerated lung function decline observed in CFRD‐affected patients [108].

3.2. Chronic Obstructive Pulmonary Disease (COPD)

Smoking and air pollution are main risk factors for COPD, characterized by mucus obstruction, fibrosis, and emphysema [109]. In HBECs from active smokers, both CFTR and BK channel activity are reduced [110, 111]. Exposure of HBECs to particulate matter increases reactive oxygen species (ROS) and DNA damage in KCNMA1‐deficient cells, suggesting a protective role for BK channels [112]. Mitochondrial BK activity reduces ROS production upon exposure of HBECs to particulate matter [113]. Since these findings come from HBECs monolayers, confirmation in native COPD airway tissues is necessary to establish the relevance of BK channels in human disease and to validate them as therapeutic targets.

3.3. Asthma

Asthma is a common chronic respiratory disease characterized by heightened inflammatory responses, airway remodeling, and airway hyperresponsiveness. The most significant clinical manifestation of asthma is airway obstruction, for which bronchoconstriction mediated by airway smooth muscle cells is a major cause [114]. Thus, the use of K⁺ channel openers as a way to treat asthma was suggested to modulate smooth muscle and nerve functions [115]. Although mucus production and release from epithelial goblet cells are also significant contributors to the airway obstruction observed in asthma, the involvement of K⁺ channels in airway epithelium has not been thoroughly studied or considered as therapeutic targets, except for a few reports [116]. Since mucus release depends on extracellular Ca²⁺ entry, a process governed by K⁺ channel‐induced hyperpolarization, pharmacological modulation of goblet cell K⁺ channels could offer a strategy to attenuate mucus hypersecretion in asthma [48, 117, 118].

Genetic silencing of Kcnn4 or treatment of mice with the KCa3.1 inhibitor TRAM‐34, reduced inflammatory cells in the bronchoalveolar lavage, prevent mast cell degranulation, bronchial remodeling and smooth muscle proliferation in lung tissue. As a consequence, airway hyperresponsiveness was significantly reduced in ex vivo experiments, nevertheless, whole animal determination of lung capacity didn't show improvements after KCa3.1 inhibition [119, 120, 121]. Interestingly, bronchial cells isolated from patients affected by asthma showed increased KCa3.1 currents that when blocked inhibited several features of TGFβ1‐induced epithelial‐mesenchymal transition [122]. More recently, the inwardly rectifying K⁺ channel KCNJ2 (Kir2.1) has been identified as a key regulator of goblet cell hyperplasia in asthma. Mechanistically, KCNJ2 activates the NLRP3 inflammasome by facilitating Ca²⁺ influx, leading to the transcription factor SPDEF‐dependent MUC5AC expression in primary human bronchial epithelial cells from asthmatic patients. Epithelial‐specific Kcnj2 deletion in mice or pharmacological inhibition attenuates airway hyperresponsiveness, Th2 inflammation, goblet cell metaplasia, and mucus production [123]. Thus, while K⁺ channel openers were originally envisioned as smooth muscle relaxants, recent evidence places epithelial K⁺ channels blockers, as pharmacological targets to reduce mucus hypersecretion, inflammation, and prevent airway remodeling in asthma.

3.4. Pharmacological Targeting of K⁺ Channels to Restore MCC

As previously indicated, small molecules used to restore CFTR function have shown to activate BK, an alternative to restore MCC in pwCF non eligible for HEMT therapy, but also an option for patients affected by other airway diseases, including asthma and COPD [92, 93, 94, 124]. Moreover, other drugs already in use in human medicine offer additional opportunities for K⁺ channel modulation, as exemplified below. Another FDA‐approved drug, currently used for treating acute muscle spasms and pain, is chlorzoxazone, a reversible BK activator, which might improve MCC in airway disease [125]. Senicapoc (ICA‐17043) is a potent and selective blocker of KCa3.1 that is safe and well tolerated in humans, that could be used to reduce airway Na⁺‐absorption and restore MCC [126]. Openers of K_ATP channels, diazoxide, minoxidil, and nicorandil, currently used for the management of hypertension, angina or as antiarrhythmic agents might offer the opportunity to increase MCC by enhancing cilia function [48, 127, 128]. In fact, diazoxide increases ciliary beating frequency in mouse ciliated cells [48] while nicorandil reduced airway resistance in animal models of asthma [129]. Thus, these examples illustrate that drugs already approved for other indications could be repurposed to modulate K⁺ channels and improve MCC in muco‐obstructive diseases.

4. Concluding Remarks and Future Directions

The respiratory epithelium is a multi‐cell‐type barrier (Figure 1), yet the expression and functional roles of K⁺ channels in many of these native cell types remain poorly defined. While cultured cell studies have identified key channel functions, translating these findings to the native epithelium is challenging, leaving substantial uncertainties. As discussed in this review, K⁺ channels regulate essential airway epithelial functions that support MCC and airway homeostasis (Figure 3). Recent evidence suggests that pharmacological targeting of K⁺ channels could serve as a novel therapy to restore MCC in pwCF and other muco‐obstructive diseases. K⁺ channel modulation may act synergistically with apical Cl⁻ channels, promote direct K⁺ secretion into the airway lumen, or reduce Na⁺ absorption, all of which enhance MCC and could prevent disease exacerbation and progression. Beyond these strategies, other possibilities include modulating goblet cell mucus secretion or increasing mucus transport speed by targeting ciliated cell activity, ultimately alleviating mucostasis (Figure 3).

FIGURE 3.

Summary of K⁺ channels function in health, disease and possible interventions to restore MCC functions. Normal airway function is controlled by apical and basolateral K⁺ channels. A reduction of its activity favors mucostasis, that can synergize with severely decreased Cl⁻ and bicarbonate (HCO₃ ⁻) secretion, as observed in CF and COPD, and increased or unbalanced Na⁺ absorption. Modulation of K⁺ channels helps to increase ASL volume by secreting K⁺ or reducing Na⁺ absorption. These will restore ciliated cells' activity, that can also be modulated by K⁺ channels. Increased ASL volume and ciliated cells' activity will enhance mucus transport out of the airways. Mucus production can also be modulated by K⁺ channel activity. Dashed lines indicate a reduction in transport.

As previously stated, a major obstacle to fully comprehend K⁺ channel function in the airways is the lack of information regarding which cell types express the channels and their precise subcellular location in native tissues, a challenging task considering that in some cases a small number of K⁺ channels are needed to modulate membrane voltage precluding detection by antibodies [130]. Moreover, the functional distribution of K⁺ channels has not been mapped along the proximal–distal airways axis, as has been done for other conductances [131, 132]. Furthermore, there is no data on the possible roles of K⁺ channels in rare cell types, such as ionocytes, brush cells, and neuroendocrine cells, which may modulate the function of other epithelial cells, as well as non‐epithelial cells like immune, nervous, and the smooth muscle [133, 134]. It also remains unknown whether K⁺ channels modulate the functions of basal cells, the airway stem cells that are critical for tissue development and repair. As already discussed, lack of Kir7.1 activity produces severe disruption of airway development in mouse and other studies using airway cell lines have suggested that K_ATP channels are necessary for efficient epithelial repair [135].

As previously discussed, the activity of apical BK favors Pseudomonas aeruginosa virulence, but the effects of K⁺ channel modulators in the airway's microbiota might be more profound. The ASL contains metabolites like short‐chain fatty acids, amino acids, and monocarboxylates, many of which are absorbed by Na⁺‐coupled transporters. Accumulation of such molecules influences microbial composition and favors dysbiosis that correlates with worsening of asthma or CF symptoms [136, 137]. In the intestine, the activity of these Na⁺‐coupled transporters is tightly regulated by basolateral K⁺ channels, and a similar mechanism is expected to regulate its function in the airways [68, 138]. Therefore, therapeutic strategies aimed at modulating basolateral K⁺ channel function should consider potential alterations in the microbiota due to metabolite accumulation.

More recently, K⁺ channels like KCa3.1, K_ATP, and members of the K₂P family have been shown to act as viral receptors and are also involved in allergen‐induced ATP release from the bronchial epithelium [139]. The modulation of these channels might therefore be exploited to reduce viral infections that can trigger asthma exacerbations, or to decrease allergen‐induced bronchial symptoms [139, 140]. Collectively, these findings extend the therapeutic relevance of K⁺ channel modulators, implicating them as potential interventions for reducing asthma exacerbations triggered by viruses or allergens, and raising the possibility that pharmacological targeting could modify long‐term disease outcomes and mortality.

This work is dedicated to the memory of our good friend Brian J. Harvey. We celebrate his contribution to the field of ion channel science and his colorful personality.

Author Contributions

Tábata Apablaza: writing – review and editing. Carlos A. Flores: conceptualization, funding acquisition, writing – review and editing, writing – original draft. Sandra Villanueva: writing – review and editing, funding acquisition. Marcelo A. Catalán: writing – review and editing, funding acquisition. Erwin Vera: writing – review and editing.

Funding

This work was supported by FONDECYT Regular 1221257 (C.A.F.) and 1211838 (M.A.C.); FONDECYT Postdoctoral 3220672 (S.V.); ANID Anillo de Tecnología ACT250073 NanoAir (C.A.F.) and the Cystic Fibrosis Trust U.K. DA004 (C.A.F.); ANID PhD Fellowship 21250795 (T.A.).

Ethics Statement

The authors have nothing to report.

Conflicts of Interest

The authors declare no conflicts of interest.

Data Availability Statement

Data sharing was not applicable to this article as no datasets were generated or analyzed during this study.