Chapter Six - Calcium-Activated Potassium Channels: Potential Target for Cardiovascular Diseases
Introduction
Ca2 +-activated K+ channels (KCa) are a type of K+ channels widely expressed in various tissues including epithelia, smooth muscle, neuron, and endothelium and are involved in a variety of cellular functions including excitability, smooth muscle contractility, and Ca2 + homeostasis. Based on the single channel conductance, KCa channels are classified into three subtypes: big conductance (BKCa, ~ 200–300 pS), intermediate conductance (IKCa, ~ 32–39 pS), and small conductance (SKCa; SK1, SK2, and SK3, ~ 4–14 pS) KCa channels. Due to their different electrophysiological properties and tissue distribution, the three types of KCa channels have distinct physiological or pathological functions. In this chapter, we summarize the physiological and pathological role of these three types of KCa channels in cardiovascular system and put forward the possibility of KCa channels as potential target for cardiovascular diseases.
Section snippets
Big Conductance Ca2 +-Activated K+ Channel
Big Conductance Ca2 +-Activated K+ Channel (BKCa) channels are channel complexes which have been well described (Zhang & Yan, 2014), and the schematic structure of BKCa channel complexes was shown in Fig. 1. BKCa channel complexes compose of either homotetramers of the pore-forming and calcium- and voltage-sensing ɑ subunit (BKɑ, which is encoded by KCNMA1 gene) alone or BKɑ together with tissue-specific auxiliary β subunits and γ subunits. Four different β subunits (β1–β4) have been cloned and
BKCa Channels and Heart
Presently, it is generally considered that BKCa channels are not expressed in the plasma membrane of adult cardiomyocytes but present at the inner mitochondrial membrane (mitoBKCa) of cardiomyocytes (Balderas, Zhang, Stefani, & Toro, 2015). The protective effects of mitoBKCa activation against ischemia are evidenced by using BKCa channel openers and BKCa channel knockout mice.
The first report showed that the protective effects of mitoBKCa activation against cardiac ischemia came from Xu et
Perspective for BKCa Channels as Potential Target for Cardiovascular Diseases
Based on the comprehensive analysis of the above discussing, BKCa channel activators would be therapeutic for alleviating myocardial ischemic injury and hypertension, because the numerous studies have shown that mitoBKCa activation reduces infart size in ischemic animal hearts, and BKCa activation in VSMCs dilate vessels. However, due to the wide expression of BKCa channels in different tissues/organs in the body, the present available BKCa channel activators including NS11021 and NS1619 are
Intermediate Conductance Ca2 +-Activated K+ Channel
The intermediate conductance Ca2 +-activated K+ channels (IKCa; KCa3.1, also known as SK4, IK, IKCa1, SMIK) were first discovered in erythrocytes by Gardos (1958) and then also found expressed in various tissues such as VSMCs, endothelial cells, macrophages, fibroblasts, T lymphocytes, and even some tumor cells (Tharp et al., 2006, Toyama et al., 2008, Wang et al., 2007, Zhao et al., 2012). KCa3.1 channel is encoded by KCNN4 and consisted of four subunits that are organized in six transmembrane
IKCa Channels and Heart
In the heart, KCa3.1 is mainly expressed in the plasma membrane of cardiac fibroblast but not present in cardiomyocytes (Zhao et al., 2012). KCa3.1 channel takes part in the regulation of proliferation and collagen production of cardiac fibroblasts (Zhao et al., 2012). It was reported that advanced glycation end products (AGEs) increased the expression of KCa3.1 in cardiac fibroblast and thereby promoted the proliferation of cardiac fibroblast via the phosphorylation of ERK1/2, p38-MAPK, and
Perspective for IKCa Channels as Potential Target for Cardiovascular Diseases
The blocker of KCa3.1 potassium channel has been implicated in therapeutic potential in cardiovascular diseases (Chou et al., 2008, Klein et al., 2009, Toyama et al., 2008). For example, TRAM-34 prevented acute angioplasty-induced coronary smooth muscle phenotypic modulation and limited stenosis in the rat (Tharp et al., 2008). TRAM-34 and clotrimazole suppressed atherosclerosis in aortas of Apoe(−/−) mice through inhibiting VSMC proliferation, and migration of VSMCs and macrophages and T
Small Conductance Ca2 +-Activated K+ Channels
The small conductance Ca2 +-activated K+ (SKCa; SK, SKCa, KCa2) channels are recognized as a subfamily of KCa channels (Bond, Maylie, & Adelman, 1999). The SKCa channel is encoded by three distinct genes, KCNN1, KCNN2, and KCNN3 with different sensitivities toward apamin. Different with BKCa channels, SKCa channels are activated solely by internal Ca2 + with higher sensitivity, submicromolar concentration, to induce hyperpolarization (Latorre, Oberhauser, Labarca, & Alvarez, 1989). SKCa channels
SKCa Channels and Heart
SKCa channels integrate intracellular Ca2 + and membrane potentials; they are activated by an increased intracellular Ca2 +; RyR2-mediated Ca2 + release is demonstrated to active and modulate SK channels in cardiac myocytes (Mu et al., 2014). Activation of SKCa channels causes membrane hyperpolarization, which inhibits cell firing and limits the firing frequency of repetitive action potentials. The expression profile studies demonstrated that SK1 was detected mainly in neuronal tissues, SK2 was
Perspective for SKCa Channels as Potential Target for Cardiovascular Diseases
Blockade of SKCa channels has been suggested as a novel target for cognitive enhancement, depression, cardiac arrhythmias, and myotonic muscular dystrophy. In cardiovascular system, SK2 channel was evidenced to be involved in certain treatment for AF, such as in the treatment with spinal cord stimulation, inhibition of SK2 contributed to the therapeutic effect by inhibiting autonomic remodeling (Wang, Zhou, et al., 2015). The negative SK2 modulators were effective agents for AF and offered a
Acknowledgment
This work was supported by the National Basic Research Program of China (Grant No. 2012CB517803) and the National Natural Science Foundation of China (Grant No. 81421063, 81373406).
Author Contributions: Y.L. Bai wrote the SKCa part, B.Z. Cai wrote the IKCa part, D.L. Dong wrote the BKCa part and organized the whole paper.
Conflict of Interest: The authors declare no conflict of interest.
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Cited by (29)
Thyrotropin induces atherosclerosis by upregulating large conductance Ca<sup>2+</sup>-activated K<sup>+</sup> channel subunits
2024, Molecular and Cellular EndocrinologyPhysiological role of K<sup>+</sup> channels in irisin-induced vasodilation in rat thoracic aorta
2022, PeptidesCitation Excerpt :In the plasma membranes of vascular smooth muscle cells, activation of KCa channels leads to the efflux of K+ ions results in hyperpolarization that inhibits the opening of VGCCs. Under these conditions, cytosolic Ca2+ concentrations are relatively low and Ca2+-dependent contraction is inhibited, followed by vasodilatation [32]. In this study, we found that SKCa, BKCa, and IKCa channels are involved in irisin-induced vasodilation.
Mitochondrial K<sup>+</sup> channels and their implications for disease mechanisms
2021, Pharmacology and TherapeuticsCitation Excerpt :Of course, an enhanced Ca2+ influx through the PM, a priori might have activating effects on the calcium-activated mitochondrial channels as well. Calcium-dependent potassium channels are expressed prevalently in excitable tissues and are generally considered promising targets for cardiovascular diseases (Dong, Bai, & Cai, 2016). However, these channels can be found in non-excitable tissues as well, and many cancer cells show overexpression of BK, IK and SK (for reviews see e.g. Leanza et al., 2014; Leanza, Biasutto, et al., 2013a; Mohr et al., 2019), where they sustain constitutive calcium entry, able to promote migration and metastasis (Guéguinou et al., 2014).
Input-output signal processing plasticity of vagal motor neurons in response to cardiac ischemic injury
2021, iScienceCitation Excerpt :When considered along with the relatively increased expression of several calcium channel genes (except Cacna1c) (Figure S17), this is suggestive of a neuronal state capable of pacemaker or even burst firing (Cui et al., 2018; Yang et al., 2018; Pape and McCormick 1989; Zhu et al., 1999). Also contributory to this conjecture is the upregulation of Grin2a, Hcn2, and Kcnn4, all of which are involved in autonomous firing (Dong et al., 2016; Chan et al., 2004; Yang et al., 2018). Along with the unique inhibitory receptors from GC-4 there is also increased expression of Gabra1 and Gabrb1 GABA receptor subunits, which may be necessary to lower the resting membrane potential of these neurons or prevent large depolarization events to permit their function as autonomous pacemakers capable of burst firing (Cui et al., 2018; Yang et al., 2018; Zhu et al., 1999).
Modulation of TRPV4 and BKCa for treatment of brain diseases
2020, Bioorganic and Medicinal ChemistryCitation Excerpt :However, studies indicate that upregulation of TRPV4 channels by TRPV4 agonist GSK1016790A elicit Ca2+ influx that activate BKCa, then result in vasodilation of arteries from other organs in rats.23,66 In cerebral artery smooth muscle cells, where BKCa channels are mainly expressed,67 influx of Ca2+ through TRPV4 induced by 11,12-epoxyeicosatrienoic acid (11,12-EET) increase the frequency of Ca2+ release events via ryanodine receptors located on the sarcoplasmic reticulum, then activate nearby BKCa channels and lead to cerebral arterial dilation in rat.68 The similar study in traumatic brain injury also proves that smooth muscle TRPV4 channels activate BKCa and result in hyperpolarization of plasma membrane and subsequently reduce pressure-induced myogenic constriction of middle cerebral arteries isolated from rat.69
Small-conductance calcium-activated potassium channels in the heart: Expression, regulation and pathological implications
2023, Philosophical Transactions of the Royal Society B: Biological Sciences