Chapter Six - Calcium-Activated Potassium Channels: Potential Target for Cardiovascular Diseases

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Abstract

Ca2 +-activated K+ channels (KCa) are classified into three subtypes: big conductance (BKCa), intermediate conductance (IKCa), and small conductance (SKCa) KCa channels. The three types of KCa channels have distinct physiological or pathological functions in cardiovascular system. BKCa channels are mainly expressed in vascular smooth muscle cells (VSMCs) and inner mitochondrial membrane of cardiomyocytes, activation of BKCa channels in these locations results in vasodilation and cardioprotection against cardiac ischemia. IKCa channels are expressed in VSMCs, endothelial cells, and cardiac fibroblasts and involved in vascular smooth muscle proliferation, migration, vessel dilation, and cardiac fibrosis. SKCa channels are widely expressed in nervous and cardiovascular system, and activation of SKCa channels mainly contributes membrane hyperpolarization. In this chapter, we summarize the physiological and pathological roles of the three types of KCa channels in cardiovascular system and put forward the possibility of KCa channels as 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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