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Review

KCa2 and KCa3.1 Channels in the Airways: A New Therapeutic Target

by
Razan Orfali
1,2,
Ali AlFaiz
2,
Mohammad Asikur Rahman
1,
Liz Lau
1,
Young-Woo Nam
1,* and
Miao Zhang
1,*
1
Department of Biomedical and Pharmaceutical Sciences, Chapman University School of Pharmacy, Irvine, CA 92618, USA
2
Biomedical Research Administration, Research Centre, King Fahad Medical City, Riyadh Second Health Cluster, Riyadh 12231, Saudi Arabia
*
Authors to whom correspondence should be addressed.
Biomedicines 2023, 11(7), 1780; https://doi.org/10.3390/biomedicines11071780
Submission received: 22 May 2023 / Revised: 8 June 2023 / Accepted: 13 June 2023 / Published: 21 June 2023
(This article belongs to the Special Issue Molecular Mechanisms, Diagnoses, and Treatments of Respiratory Diseases)
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Abstract

:
K+ channels are involved in many critical functions in lung physiology. Recently, the family of Ca2+-activated K+ channels (KCa) has received more attention, and a massive amount of effort has been devoted to developing selective medications targeting these channels. Within the family of KCa channels, three small-conductance Ca2+-activated K+ (KCa2) channel subtypes, together with the intermediate-conductance KCa3.1 channel, are voltage-independent K+ channels, and they mediate Ca2+-induced membrane hyperpolarization. Many KCa2 channel members are involved in crucial roles in physiological and pathological systems throughout the body. In this article, different subtypes of KCa2 and KCa3.1 channels and their functions in respiratory diseases are discussed. Additionally, the pharmacology of the KCa2 and KCa3.1 channels and the link between these channels and respiratory ciliary regulations will be explained in more detail. In the future, specific modulators for small or intermediate Ca2+-activated K+ channels may offer a unique therapeutic opportunity to treat muco-obstructive lung diseases.

Graphical Abstract

1. Introduction

The epithelial surface of the respiratory tract between the nose and the alveoli is constantly exposed to potentially harmful pathogens, particulates, and gaseous materials [1,2,3]. In response to these challenges, the human body utilizes a series of defense mechanisms to protect the airways, and the primary defense mechanism in the lung is mucociliary clearance (MCC) [1,4]. MCC is a process of specialized organelles called cilia that beat in metachronal waves to impel pathogens and particles trapped by the mucous layer out of the airways. Cilia within the mucociliary system present critical functions in human health; abnormalities in each compartment of the mucociliary system could compromise the mucus clearance process and lead to chronic lung disease [2,3]. Mucociliary dysfunction is commonly associated with chronic airway diseases, and it is one of the pathological observations in patients with cystic fibrosis, primary ciliary dyskinesia, chronic bronchitis, and asthma [5,6]. Airway diseases with associated mucociliary dysfunction remain largely unaddressed, despite the therapeutic progress in treating inflammatory lung diseases [5].
The lung’s lining is covered by a thin layer of fluid called airway surface liquid (ASL); it separates the airway epithelium’s luminal surface from the external environment. ASL is mainly composed of water, electrolytes, and mucins; it is essential for normal airway function, particularly for proper MCC [3,7,8]. ASL epithelia contain various cell types with distinct morphologies and functions. Of the cell population in the trachea, approximately 60% are ciliated cells; these cells also retain other important roles other than coordinating ciliated movements, such as regulating ion transfer [1,9].
There are detections of over 30 diverse K+ channels in the airway epithelia, and these K+ channels maintain the electrochemical gradient and support lung ion and fluid homeostases [1,10,11,12]. A large portion of airway chloride secretion occurs through the apically located bicarbonate and chloride channels [10]. K+ channels are involved in many vital functions in lung physiology, such as oxygen sensing, inflammatory responses, enhancing Cl− transport, and respiratory epithelia repair [9,13]. The basolateral K+ channel has known regulation effects on Na+ absorption; reduced Na+ absorption in the lung shows improvement in muco-obstructive disease. A large portion of airway chloride secretion occurs through the apically located bicarbonate and chloride channels, significantly influenced by some Ca2+-activated K+ channels (KCa) that are located apically in the lung [10]. Hence, the specific K+ group KCa also regulates MCC and ASL volumes [1]. The small-conductance KCa2 channels and intermediate-conductance KCa3.1 channels are voltage-independent and activated solely by the elevation of the intracellular Ca2+ concentration. In this context, we will discuss current knowledge of the functional roles of KCa2 and KCa3.1 channels in the respiratory tract, focusing on their physiological roles in respiratory diseases.

2. Introduction to KCa Channels

There are several kinds of K+ channels present in the respiratory epithelium lining airways, and the most indispensable K+ channels in airway epithelial cells are the Ca2+-activated K+ channels. They serve as the cell crossroad where Ca2+ influx, other ion outfluxes, and membrane potential, all processes governed by KCa channels, integrate to modulate an extensive array of cellular processes [14]. KCa channels are subdivided into three major groups, according to their single-channel conductance: large conductance (150–300 pS) K+ channels (BK or KCa1.1), small conductance (2–20 pS) K+ channels (SK or KCa2), and intermediate conductance (20–60 pS) K+ channels (IK or KCa3.1) [15,16,17]. Each group has specific distinct biophysical and pharmacological properties [18]. KCa2.x and KCa3.1 channels are voltage-independent and activated exclusively by intracellular Ca2+ via the calmodulin (CaM) that is typically bound to these channels and serves as their Ca2+ sensor [19]. KCa2x and KCa3.1 channels, before their cloning, were referred to as small-conductance (SK) or intermediate-conductance (IK) Ca2+-activated K+ channels, based on their singular conductance of ~10 pS or ∼40 pS in symmetrical solutions to differentiate them from the large-conductance potassium (BK) channel [19,20].
Four mammalian KCNN channel subtypes are encoded by the KCNN genes, including KCNN1 for KCa2.1, KCNN2 for KCa2.2, KCNN3 for KCa2.3 [21], and KCNN4 for KCa3.1 [22], respectively [23] (Table 1).

KCa2 and KCa3.1 Channel Structures

KCa2 and KCa3.1 channels are assembled as homotetramers of four α-subunits; each subunit is composed of six transmembrane α-helical domains denoted as S1–S6 (Figure 1). The selectivity filter within the channel pore between the S5 and S6 transmembrane domains is responsible for the selective permeability of the K+ ions [30,34]. The KCa2/KCa3.1 channel subtypes are highly homologous in their six transmembrane domains, but the amino acid sequences and lengths at their cytoplasmic N- and C-termini differ among the subtypes (Table 1) [37].
Among the four KCa2/KCa3.1 channel subtypes, the full-length cryogenic electron microscopy (cryo-EM) structure is only available for the KCa3.1 channel determined in the absence and presence of Ca2+, providing insight into the Ca2+/CaM gating mechanism for these channels [36]. The calmodulin-binding domain consists of two α-helices, HA and HB, whereas the S4–S5 linker includes two α-helices, S45A and S45B. The HA and HB helices from one channel subunit, the S4–S5 linker from a neighboring channel subunit, and calmodulin closely interact with each other (Figure 1). When Ca2+ is absent, the C-lobe of CaM binds to the HA/HB helices in the proximal channel C-terminus, the N-lobe of CaM is highly flexible, and the channel pore is closed (Figure 1B). In the presence of Ca2+, the N-lobe of CaM becomes well-structured and interacts with the linker between the S4 and S5 transmembrane domains (S4–S5 linker) of a neighboring α-subunit. The interaction between the Ca2+-bound CaM N-lobe and the S4–S5 linker causes the movement of the S6 transmembrane domain and the opening of the channel pore (Figure 1C) [33,38].
KCa2 channels are activated by Ca2+, with EC50 values ranging from 300 to 750 nM, whereas KCa3.1 channels exhibit apparent Ca2+ sensitivities of 100–400 nM [29,34,39]. KCa2 and KCa3.1 channels, therefore, play a critical role in the physiologies of various tissues and disease states [22,40]. The advances in understanding the KCa3.1 structure [36] (the cryo-electron microscopy of the human homotetrameric KCNN4 channel) and the resulting improvements in other KCa2 subtypes modeling [29,30,34] have yet to be used, not only for drug discovery but also for understanding the pathophysiological diseases.

3. KCa Channels in the Respiratory System

The involvement of K+ channels has been proposed in respiratory conditions such as asthma, chronic obstructive pulmonary diseases (COPD), and cystic fibrosis (CF) [1,12]. In airway epithelial cells, both Cl− and K+ transports rely, to some extent, on Ca2+-dependent channel activity (e.g., KCa channels) [1]. KCa channels are important in regulating Cl− secretion, MCC, and ASL volumes. KCa3.1 and KCa2 channel subtypes located in the airway epithelia, such as KCa2.1 [41] and KCa2.3 [42], maintain the electrochemical gradient and thus support lung ion and fluid homeostasis [1]. Table 2 summarizes the KCNN gene family, tissue distribution, physiological roles, and their roles in the lungs.

3.1. KCa Channels and the Respiratory Cilia

The KCa2 and KCa3.1 channels are tetramers, and each subunit comprises six transmembrane alpha-helical domains (six TMD), indicated as S1–S6 in each channel subunit. The selectivity of potassium ions across these channels is based on the pore-forming P-loop between the transmembrane S5 and S6 domains. KCa2/KCa3.1 are more sensitive to Ca2+ due to calmodulin CaM acting as a Ca2+ sensor (Figure 1) [26,47]. CaM is present in all eukaryotic cells, facilitating various cellular signaling processes, such as the modulation of ion channel actions, regulation of enzymatic activities, and gene expression [14,48]. The ciliary beat of the airway epithelium is believed to be regulated by the level of intracellular Ca2+ [49]. The association with calmodulin in the regulation of ciliary beats has been reported as the most important intraciliary Ca2+ binding protein [49,50]. Moreover, the activation of KCa2 channels in non-excitable cells, such as epithelial cells, increases Ca2+ entry through non-voltage-gated Ca2+ channels, thereby increasing intracellular Ca2+ concentration [51]. This elevation of intracellular Ca2+ is one of the primary regulators of ciliary movement [52]. Thus, KCa2 and KCa3.1 channels will regulate respiratory ciliary activities as part of a complex signaling network.

3.1.1. KCa Channels and Ciliary Beat Frequency

In vitro measurements of the changes in the CBF of human respiratory cells indicate that Ca2+ ionophore speeds the CBF of human respiratory cells mediated through a calmodulin-sensitive system [53]. Airway epithelial cells contain 100 nM of free Ca2+ in their cytoplasm, but ciliated cells bear a higher concentration at baseline than club cells [54]. This supports the idea that KCa2 channels may be active during normal conditions in specific airway cells, as these channels show a high sensitivity to Ca2+ (Table 2). Significantly, in CF mouse airways, a previous study by Vega et al. [5] determined that KCNN4-silencing enhanced MCC when Na+ absorption was decreased. Additionally, CBF was also increased by KCa3.1 inhibition. An explanation is that KCa3.1 inhibition reduces Na+ absorption in CF, thereby increasing CBF speeds by hyperpolarizing the apical membrane [5,55].

3.1.2. KCa2 Channels and Cilium Length

Muco-obstructive lung disease is considered the primary cause of morbidity and is responsible for 80% of mortality [55]. The presence of KCa2 channels in a human bron-chial epithelial cell, and structural similarities in the groups of KCa2 and KCa3.1, pro-vides a new direction in the investigating the expression and function of KCa2 channel subtypes in the ciliated human lung epithelial cells. Optimal MCC requires mucus, cilia, and a thin layer of ASL to facilitate ciliary beating [2]. Maintaining a normal range of respiratory cilia length (4 to 7 μm, depending on the airway region) is critical for adequate mucociliary clearance [56]. A qualitative difference exists between short and longer cilia waveform shapes [57], and various acquired lung disorders are marked by abnormalities in both cilia structure and function [56]. Our previous work determined the critical role of KCa2.3 channels in regulating the primary cilia in endothelial cells [58]. Taking advantage of the previous results could help to connect KCa2 channels and respiratory cilia, two crucial components in the Ca2+ signaling network of airway epithelial and smooth muscle cells, with potential implications in the pathogenesis of airway diseases.

4. Expression and Physiological Functions of KCa2 and KCa3.1 Channels in the Airways

Many human cells express KCa channels that have the exceptional ability to trans-late changes in the level of the intracellular second messenger, Ca2+, to changes in membrane K+ conductance and, thus, resting potential membrane. While KCa channel subtypes are all regulated by intracellular Ca2+, they are otherwise quite distinct entities, differing in tissue distribution and functions [59]. KCa2 channel subtypes, for example, are widely expressed in the nervous system, where they are involved in regulating the firing frequency of various neurons. On the other hand, the KCa3.1 channel subtype is expressed in peripheral cells, including the erythrocytes and lymphocytes, and has been determined in numerous cancer cells where they have been implicated in growth control [60,61]. Here we demonstrate the expressions and physiological roles of KCa2 and KCa3.1 channels in the airways.

4.1. Expression and Functions of KCa2 in the Respiratory Epithelia

KCa2 channels are widely expressed in various tissues and play an important role in modulating excitable and non-excitable cells. The presence of KCa channel groups was confirmed at the apical and basolateral membranes of airway epithelial cells [1,62] (Figure 2A). The bronchial epithelium expresses KCa2.1 and KCa2.3 channel subtypes[35,41]. KCa2.2 and KCa2.3 mRNA were detected in the lungs and trachea [3,4]. KCa2.2 and KCa2.3 mRNA were detected in lungs and trachea [6]. KCa2.3 is the only subtype expressed in the pulmonary artery [5]. Figure 2-B shows the major expression sites of KCa2 and KCa3.1 channel subtypes in the airway.
Different ion channels seem to be present in motile cilia [63]. In the nasal cavity, olfactory receptor neurons (ORNs) are adapted to grow various long cilia; they are not motile but can move with the liquid stream of the nasal mucosa to sample odorants entering the nose. The presence of KCa channel groups in the cilia of ORNs was reported [64].
Biomedicines 11 01780 g002 550
Figure 2. Expression sites of KCa2 and KCa3.1 channels in the respiratory system. (A) Schematic drawing of ciliated airway epithelial cells of KCa2 and KCa3.1 channels. (B) KCa2 and KCa3.1 channels were expressed in airway smooth muscle [65], airway olfactory nerves [66] and olfactory cilia [64]; KCa2.2 and KCa2.3 subtypes presented in the lungs and the trachea [45]; and KCa3.1, KCa2.1, and KCa2.3 subtypes presented in the respiratory epithelia [41,42]. The pulmonary artery expressed the KCa2.3 subtype [42].
Figure 2. Expression sites of KCa2 and KCa3.1 channels in the respiratory system. (A) Schematic drawing of ciliated airway epithelial cells of KCa2 and KCa3.1 channels. (B) KCa2 and KCa3.1 channels were expressed in airway smooth muscle [65], airway olfactory nerves [66] and olfactory cilia [64]; KCa2.2 and KCa2.3 subtypes presented in the lungs and the trachea [45]; and KCa3.1, KCa2.1, and KCa2.3 subtypes presented in the respiratory epithelia [41,42]. The pulmonary artery expressed the KCa2.3 subtype [42].
Biomedicines 11 01780 g002
The involvement of K+ channels has been proposed in respiratory conditions such as asthma, chronic obstructive pulmonary diseases (COPD), and cystic fibrosis (CF) [1,12]. In airway epithelial cells, both Cl− and K+ transports rely, to some extent, on Ca2+-dependent channel activity (e.g., KCa channels) [1]. KCa channels are important in regulating Cl− secretion, MCC, and ASL volumes. KCa2 channel subtypes located in the airway epithelia, such as KCa2.1 [41] and KCa2.3 [42], maintain the electrochemical gradient and thus support lung ion and fluid homeostases [1].
In CF, the equilibrium between Na+ absorption and Cl− secretion throughout the airway epithelia is necessary to maintain adequate ASL volume and MCC. The Cl− secretion in the lungs involves several steps, starting from Cl− entry through a basolateral channel cotransporter, followed by its exit via apical Cl− channels, such as the cystic fibrosis transmembrane conductance regulator (CFTR) [3]. The dysfunction of CFTR channels in CF results in decreased Cl− and fluid secretions and increased Na+ absorption, leading to inefficient mucociliary clearance and mucus accumulation [67].
In COPD, KCa channel groups can also act as oxygen sensors for lung diseases, such as COPD associated with pulmonary hypertension [12]. In COPD, pulmonary hypertension is generally believed to be due to hypoxic pulmonary vasoconstriction [68]. KCa channels potentiated by the low partial pressure of oxygen (PO2) have been investigated in cerebral resistance myocytes [69]. When hypoxia occurs, KCa channels activate (preventing repolarization) and relax the pulmonary arteries [70,71].
KCa channels were proposed as new targets for bronchodilator therapy for chronic diseases such as asthma and COPD [72]. The mentioned COPD-related studies [69,70,71,72] examined KCa channel groups in general. Though one study suggested that human pulmonary artery and bronchial relaxations might be mediated by pharmacological activation of the KCa2.3 channel subtypes [42] (Table 2).
In anosmia, Odorant-induced K+ conductance is activated by Ca2+ [73], and the elevation of intracellular Ca2+ is often associated with odorant stimulation in some vertebrates and human olfactory neurons [51,74]. Olfactory Receptor Neurons (ORNs) are located in the nasal epithelia and exhibit spontaneous action potential firing. All KCa channel groups have been detected in olfactory cilia [52], and the electrophysiological of the whole-cell results confirmed that KCa channels participate in inhibitory chemo-transduction in the cilia [75]. According to these findings, an apical Ca2+ influx opens the KCa channels, causing membrane hyperpolarization in response to Ca2+ influx and thus triggering the inhibition [74].
Moreover, a Ca2+ channel blocker, nifedipine, was tested on odorants that induce an inhibitory current in olfactory neurons [74]. This drug effectively abolished the outward current and stimulated the cells with an odorant solution free of nifedipine, and the response was restored [74]. KCa2 channel subtypes which are completely Ca2+-dependent and voltage-independent may play a critical role in treating certain diseases, given the drugs that could target specific ion channels. For example, anosmia could be treated by targeting the KCa2 channel subtypes in olfactory cilia and testing their allosteric modulators [52]. However, the pharmacology of these channels in olfactory neurons has not been fully characterized.

4.2. Expression and Functions of KCa3.1 in the Respiratory Epithelia

The expression of Ca2+-activated potassium (KCa) channels often correlate positively with cell proliferation. As an example, the expression of KCa3.1 increases 4-fold upon T-lymphocyte activation, and this channel is inhibited with the specific inhibitor that inhibits T-lymphocyte proliferation [76]. This is because the KCa3.1 channel contributes to electrochemical gradients for Ca2+ influx, which is critical for the proliferation of the T cells [77]. KCa3.1 is also broadly expressed in other cells of the immune system, such as B cells, macrophages, microglia, and mast cells [78]. The major function of KCa3.1 in immune cells is to hyperpolarize the cell membrane and create the driving force for calcium entry, which is necessary for proliferation, activation, and cytokine production [79]. Previous findings [80] suggest that antigen sensitization up-regulates KCa3.1 expression, which may contribute to enhancing cell migration in response to lymphatic chemokines, particularly in the immunogenic lung dendritic cells subset. Therefore, targeting KCa3.1 crucial for controlling allergic airway inflammation [81] (Table 2 and Figure 2).
KCa channels have been found to be involved in regulating smooth muscle responses to both contractile and relaxant agonists that elevate intracellular Ca2+ [82]. Phenotypic modulation of smooth muscle cells is accompanied by changes in KCa3.1 channel expression characterizing “proliferative” cells [83]. KCa3.1 channels regulate the proliferative responses of vascular smooth muscle cells, fibroblasts, endothelial cells, and T lymphocytes, as well as a some transformed cell types [61,84]. KCa3.1 function is increased by protein kinase A (PKA) [85] and nucleoside diphoshate kinase B (NDPK-B) and inhibited by the histidine phosphatase PHPT1 [86,87]. Since NDPK-B and PHPT1 directly phosphorylate or dephosphorylate KCa3.1 on histidine in the C-terminus, KCa3.1 modulation in mammals is one of the rare examples of histidine kinase/phosphatase regulating a biological process [86].
In allergic lung diseases, KCa3.1 channels regulate Ca2+ entry into cells and thereby modulate Ca2+-signaling processes. The entry of positively charged Ca2+ into the cells depolarizes the membrane, which limits its own ability to enter the cell through some types of Ca2+ channels that are closed at more positive membrane potentials. KCa3.1 activation by elevated intracellular Ca2+ maintains a negative membrane potential, which helps to sustain Ca2+ entry into the cell. KCa3.1-mediated elevation of intracellular Ca2+ is necessary for the production of inflammatory chemokines and cytokines by T cells, mast cells, and macrophages [79,88]. Indeed, proliferation is accompanied by the transcriptional up-regulation of functional KCa3.1 expression and can be inhibited by KCa3.1 inhibitors [86]. It has been reported that the use of KCa3.1 blockers can provide a potential therapeutic target for mast cell-mediated diseases such as asthma [88]. Moreover, blocking KCa3.1 may offer a novel approach to treating idiopathic pulmonary fibrosis [89].
In muco-obstructive hyper tension, the inhibition of the KCa3.1 channel [5] and Kcnn4 silencing in ion transport and MCC in an animal model of CF/COPD-like muco-obstructive lung disease determined that Kcnn4 silencing enhances airway disease [5]. The effectiveness of the mucociliary clearance depends mainly on hydration. Water availability in the airways is controlled by transepithelial ion transport. Apical Cl− secretion and Na+ absorption play major roles in ASL volume homeostasis [90]. The decline in Na+ absorption is of potential benefit in muco-obstructive disorders, such as cystic fibroses. It was described earlier in the case of the kidney and intestine, where the inhibition of basolateral K+ channels decreased Na+ absorption [5,57], thus supporting the role of K+ channels on epithelial Na+ homeostasis.
In pulmonary artery hypertension, elevated pulmonary artery pressure occurs in several diseases, such as asthma, end-stage chronic obstructive pulmonary disease (COPD), and lung fibrosis [66,91,92]. In order to diagnose pulmonary artery hypertension, hemodynamic measurements are taken via right heart catheterization or echocardiography; the condition is defined as a mean pulmonary artery pressure above 25 mmHg at rest or greater than 30 mmHg during normal physical activity [92]. Studies suggest that pharmacologically activating KCa3.1 channels mediates human pulmonary artery and bronchial relaxations [42]

5. Pharmacological KCa2 and KCa3.1 Channel Modulators in Respiratory Diseases

The KCa2.3 and KCa3.1 potassium channels are characterized by their voltage independence, and thus, they are activated by intracellular Ca2+. Due to the distinct distribution of the channel subtypes in the mammalian cells and their involvement in the generation of afterhyperpolarization currents, there has been considerable interest in developing subtype-selective pharmacological tools to study these channels [93,94]. Additionally, KCa2.3 and KCa3.1 channels comprise attractive new targets for several diseases that currently have no effective therapies. The pharmacology of KCa channels developed relatively rapidly after the cloning of the KCa2 and KCa3.1 channels, as the field now has a wide range of peptides, small-molecule inhibitors, and positive- and negative-gating modulators with differential subtype selectivity available [44].
The KCa3.1 and KCa2 channels have relatively well-developed pharmacological tools. The field now has a wide range of peptides, small-molecule inhibitors, and positive- and negative-gating modulators with differential subtype selectivity available [93]. Table 3 shows the small molecule positive and negative modulators with differential KCa2 subtype selectivity [44]. For treating CF and other mucociliary diseases, KCa3.1 inhibitors are needed [5]. Senicapoc [95] and TRAM-34 [96] inhibit KCa3.1 channels with IC50 values of ~11 nM, and ~20 nM, respectively, and they are highly selective for KCa3.1 channels over KCa2 channel subtypes [33]. The selective negative modulator for the KCa2 channel AP14145 is equipotent in inhibiting KCa2.2 and KCa2.3 but is ineffective on KCa3.1 channels [97].
For treating anosmia, COPD and its related pulmonary hypertension, KCa2-positive modulators may be beneficial [42,46,62]. NS309 is a potent, non-selective activator of human KCa3.1 and KCa2 channels [98]. The KCa2.2 and KCa2.3 channels are potently and selectively activated by CyPPA [38], and their derivatives are chemically modified to create more efficient and selective positive modulators [99]. However, further investigations are needed to determine their effectiveness [33].
Table
Table 3. Small-molecule positive and negative modulators of KCa2 and KCa3.1 channels.
Table 3. Small-molecule positive and negative modulators of KCa2 and KCa3.1 channels.
Nonselective KCa2/KCa3.1KCa2 SelectiveKCa3.1 SelectiveSubtype KCa2 Selective
Positive modulatorsNS309 [98]
SKA-31 [100]
1-EBIO [101]
Riluzole [102]		 SKA-111 [44]
SKA-121 [103]		KCa2.2/KCa2.3 selective
CyPPA [38]
NS13001 [104]
Compound 2q * [99]
KCa2.1 selective
CM-TPMF [102]
Negative
modulators		RA-2 [103]NS5893 [104]
AP14145 [97]		Senicapoc [11,95]
TRAM-34 [96]		KCa2.1 selective
Bu-TPMF [102]
* 2q is a CyPPA-modified compound, other CyPPA modified compounds include: 2m–2n, 2p, 2r–2t, 2v, and 4. The potencies of these compounds on potentiating KCa2.3 and KCa2.2a channels have previously been determined [57,99].

6. Conclusions and Perspectives

In recent years, remarkable progress has been made in understanding the physiological and pathophysiological roles of KCa channels. The advances in understanding the KCa3.1 structure and the resulting improvements in other KCa2 subtypes modeling have yet to be used, not only for drug discovery but also for understanding the pathophysiological diseases, particularly airway diseases, and developing more subtype-selective biophysical and pharmacological tools. Over the past few years, researchers have studied KCa3.1 channel expression and its physiological role in airway diseases. There are, however, few studies on KCa2 channels in the respiratory system. Evidence now suggests that KCa2 channels are present in the respiratory system and play an important role in airway disorders, such as asthma, chronic obstructive pulmonary disease, cystic fibrosis, and other muco-obstructive diseases. Nevertheless, further studies are necessary to unveil the exact cell distribution, subcellular localization, and protein interactions of KCa2 channels in the airways. Additional research is required to further establish and validate KCa2 and KCa3.1 channels as ion channels in airway diseases, their clinical relevance, and the development of more potent and subtype selective KCa2 channel modulators.

Author Contributions

R.O. drafted the manuscript; A.A., M.A.R. and L.L. edited and revised the manuscript; Y.-W.N. and M.Z. approved the final version of the manuscript. All authors contributed to the manuscript and the figures. All authors have read and agreed to the published version of the manuscript.

Funding

This study was supported by a 23AIREA1039423 grant from the American Heart Association, a YI-SCA grant from the National Ataxia Foundation, and a 4R33NS101182-03 grant from NIH awarded to M.Z. And grant 023-012 from King Fahad Medical City Research Center awarded to R.O.

Institutional Review Board Statement

Not applicable.

Informed Consent Statement

Not applicable.

Data Availability Statement

Not applicable.

Acknowledgments

We thank King Fahad Medical City Research Center and Chapman University Writing Center for revising the manuscript. We thank Fan Feng and Reem Orfali for their technical support. Figures were created with BioRender and published with permission.

Conflicts of Interest

The authors declare no conflict of interest.

Abbreviations

ASLAirway surface liquid
Ca2+ Calcium
CaM Calmodulin
Cl−Chloride
COPDChronic obstructive pulmonary disease
CBFCilia beating frequency
KCaCa2+-activated K+ channels
CFCystic fibrosis
CFTRCystic fibrosis transmembrane conductance regulator
KCa3.1Intermediate-conductance Ca2+-activated K+ channels
BK Large-conductance Ca+2-activated K+ channels
MCCMucociliary clearance
ORNs Olfactory receptor neurons
K+Potassium
KCa2Small-conductance Ca2+-activated K+ channels
Na+Sodium
TMsTransmembrane helices
WTWild type

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Figure 1. KCa3.1 and KCa2 Channel Structures in the presence and absence of Ca2+. KCa2 and KCa 3.1 channels are assembled as homotetramers of four α-subunits. (A) Human KCa3.1 channel cryo-EM structure (PDB: 6cnn). For clarity, four-channel subunits are shown in different colors: green, blue, yellow, and purple, along with calmodulin (CaM) (gray). (B) Schematic representation of one channel subunit in the absence of Ca2+. (C) Schematic representation of one channel subunit in the presence of Ca2+. (D) Extracellular top view of the KCa3.1 and KCa2 channels. (A) was generated using Biorender.com. (B,C) were generated using Pymol (Schrödinger, LLC, New York, NY, USA).
Figure 1. KCa3.1 and KCa2 Channel Structures in the presence and absence of Ca2+. KCa2 and KCa 3.1 channels are assembled as homotetramers of four α-subunits. (A) Human KCa3.1 channel cryo-EM structure (PDB: 6cnn). For clarity, four-channel subunits are shown in different colors: green, blue, yellow, and purple, along with calmodulin (CaM) (gray). (B) Schematic representation of one channel subunit in the absence of Ca2+. (C) Schematic representation of one channel subunit in the presence of Ca2+. (D) Extracellular top view of the KCa3.1 and KCa2 channels. (A) was generated using Biorender.com. (B,C) were generated using Pymol (Schrödinger, LLC, New York, NY, USA).
Biomedicines 11 01780 g001
Table
Table 1. Apparent Ca2+ sensitivity, structural studies, amino acid sequences alignments and identities between KCa2/3 channel subtypes.
Table 1. Apparent Ca2+ sensitivity, structural studies, amino acid sequences alignments and identities between KCa2/3 channel subtypes.
KCa2/3
α Subunit		Amino AcidsApparent Ca2+ Sensitivity (μM)KCa2 Subtypes Structural StudiesSequence Alignment among KCa2 and KCa3.1 Channels
KCa2.1543 [24]~0.31 [25,26][27,28]KCa2.1 and KCa3.1 share a 43.3% sequence identity [29]
KCa2.2579 [25]~0.32 [25,30][15,26,29,31]KCa2.2 and KCa3.1 share a 45% sequence identity [32]
KCa2.3731 [25]~0.30 [33,34][34,35]KCa2.3 and KCa3. share a 46.6% sequence identity [34]
KCa3.1427 [25]~0.27 [33,34][36]
Table
Table 2. The KCNN gene family. Human chromosomal location, tissue distribution, functional effects, and their roles in the lungs.
Table 2. The KCNN gene family. Human chromosomal location, tissue distribution, functional effects, and their roles in the lungs.
KCa2/3
α Subunit		GeneOther NamesHuman Chromosomal LocationTissue DistributionPhysiological RolesRole in the Lungs
KCa2.1KCNN1SK119p13.11 [25]Brain [25]
Heart [43]
Lung [41]		The KCa2 channels underlie the medium AHP and regulate neuronal firing frequency [23,44].ND *
KCa2.2KCNN2SK25q22.3 [25]Brain and heart
Adrenal gland, lungs, prostate, bladder, and liver [25,45].		ND *
KCa2.3KCNN3SK31q21.3 [25]Brain and heart
Vascular endothelium, lungs, and bladder
[25,44]		KCa2.3 and KCa3.1 mediate the
endothelium-derived hyperpolarization response [33,46]		(+) KCa2.3 relaxes the pulmonary arteries and bronchi ** [32]
KCa3.1KCNN4SK4
IK		19q13.31 [25]Vascular endothelium
T and B lymphocytes
Microglia, placenta, colon, and red blood cells
Lungs and bladder [25,44]		KCa3.1 channels regulate calcium signaling, cellular activation, and cell volume [23,44](−) KCa3.1 reduces Na+ absorption ***, (+) CBF, and MCC [5].
(+) KCa3.1 relaxes the pulmonary arteries and bronchi [42]
* ND: not determined specifically in the respiratory system. ** (+): Activation. *** (−): Inhibition.
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Orfali, R.; AlFaiz, A.; Rahman, M.A.; Lau, L.; Nam, Y.-W.; Zhang, M. KCa2 and KCa3.1 Channels in the Airways: A New Therapeutic Target. Biomedicines 2023, 11, 1780. https://doi.org/10.3390/biomedicines11071780

AMA Style

Orfali R, AlFaiz A, Rahman MA, Lau L, Nam Y-W, Zhang M. KCa2 and KCa3.1 Channels in the Airways: A New Therapeutic Target. Biomedicines. 2023; 11(7):1780. https://doi.org/10.3390/biomedicines11071780

Chicago/Turabian Style

Orfali, Razan, Ali AlFaiz, Mohammad Asikur Rahman, Liz Lau, Young-Woo Nam, and Miao Zhang. 2023. "KCa2 and KCa3.1 Channels in the Airways: A New Therapeutic Target" Biomedicines 11, no. 7: 1780. https://doi.org/10.3390/biomedicines11071780

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