KCa3.1: target and marker for cancer, autoimmune disorder and vascular inflammation?

Chou, Chuan-Chu; Lunn, Charles A.; Murgolo, Nicholas

doi:10.1586/14737159.8.2.179

Cited by 74 publications

(73 citation statements)

References 57 publications

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“…33 The KCa3.1 potassium channel has been demonstrated to impact the function of macrophages by regulating intracellular Ca 2+ homeostasis. 9 Furthermore, a recent study indicated that intracellular Ca2 + overloading triggers greater macrophage production of inflammatory mediators and promotes classically activated macrophage M1 polarization. 34 In the present study, we found that decreasing STAT-1 phosphorylation underscores the role of blocking KCa3.1 in inhibiting proinflammatory genes expression during macrophage polarization and attenuating plaque instability.…”

Section: Discussionmentioning

confidence: 99%

“…Therefore, KCa3.1 is an attractive pharmacological target for use in immunotherapy. [9][10][11] KCa3.1 gating is voltage independent and only requires a small increase in intracellular calcium. Intracellular calcium binds to calmodulin molecules that are constitutively associated with the channel protein and induce channel opening, which results in K + efflux that maintains a negative membrane potential.…”

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confidence: 99%

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Role of KCa3.1 Channels in Macrophage Polarization and Its Relevance in Atherosclerotic Plaque Instability

et al. 2017

ATVB

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Objective-Emerging evidence indicates that proinflammatory macrophage polarization imbalance plays a key role in atherosclerotic plaque progression and instability. The calcium-activated potassium channel KCa3.1 is critically involved in macrophage activation and function. However, the role of KCa3.1 in macrophage polarization is unknown. This study investigates the potential role of KCa3.1 in transcriptional regulation in macrophage polarization and its relationship to plaque instability. Approach and Results-Human monocytes were differentiated into macrophages using macrophage colony-stimulating factor. Macrophages were then polarized into proinflammatory M1 cells by interferon-γ and lipopolysaccharide and into alternative M2 macrophages by interleukin-4. A model for plaque instability was induced by combined partial ligation of the left renal artery and left common carotid artery in apolipoprotein E knockout mice. Significant upregulation of KCa3.1 expression was observed during the differentiation of human monocytes into macrophages. Blocking KCa3.1 significantly reduced the expression of proinflammatory genes during macrophages polarization. Further mechanistic studies indicated that blocking KCa3.1 inhibited macrophage differentiation toward the M1 phenotype by downregulating signal transducer and activator of transcription-1 phosphorylation. In animal models, KCa3.1 blockade therapy strikingly reduced the incidence of plaque rupture and luminal thrombus in carotid arteries, decreased the expression of markers associated with M1 macrophage polarization, and enhanced the expression of M2 markers within atherosclerotic lesions. opening, which results in K + efflux that maintains a negative membrane potential. Thus, the initial influx of Ca 2+ feeds forward, thereby, preserving the negative V m (membrane voltage) required for sustained Ca 2+ influx. 12 The Ca 2+ influx leads to an increase in cytosolic Ca 2+ concentration, which is necessary for the translocation of nuclear factors to the nucleus and the initiation of new transcription. Conclusions-TheseParticularly, in macrophages, KCa3.1 has been shown to be involved in activation, migration, proliferation, and respiratory bursting, indicating that KCa3.1 suppression might be helpful in some macrophage-related disorders, such as asthma, multiple sclerosis, stroke, and so forth. [13][14][15] Previous evidence has demonstrated a role for KCa3.1 in atherosclerosis. In mouse models, pharmacological inhibition of KCa3.1 by the selective blocker TRAM-34 attenuates atherosclerotic lesion formation and may provide a novel approach for the prevention and treatment of atherosclerosis. 16 However, in advanced atherosclerotic lesions, the role of KCa3.1 in the pathogenesis of plaque instability and its underlying mechanisms are unknown. A recent study reported that IL-4 stimulation increases KCa3.1 current in microglia, 17 which suggests that KCa3.1 may be involved in the polarization of macrophages and atherosclerotic plaque disruption. In this study, we pharmacologic...

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Section: Discussionmentioning

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Role of KCa3.1 Channels in Macrophage Polarization and Its Relevance in Atherosclerotic Plaque Instability

et al. 2017

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“…In the cardiovascular system, vascular endothelial cells express both IK and SK3 channels, which are implicated in the endothelium-derived hyperpolarizing factor-mediated vasodilation (17)(18)(19)(20). The importance of SK/IK channels is demonstrated further by their potential roles in clinical abnormalities (21)(22)(23)(24). SNPs in the SK/IK genes are thought to play a role in cardiovascular abnormalities, such as familial atrial fibrillation (22,25).…”

Section: +mentioning

confidence: 99%

Unstructured to structured transition of an intrinsically disordered protein peptide in coupling Ca ²⁺ -sensing and SK channel activation

Zhang¹,

Pascal²,

Zhang

2013

Proc. Natl. Acad. Sci. U.S.A.

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Most proteins, such as ion channels, form well-organized 3D structures to carry out their specific functions. A typical voltagegated potassium channel subunit has six transmembrane segments (S1-S6) to form the voltage-sensing domain and the pore domain. Conformational changes of these domains result in opening of the channel pore. Intrinsically disordered (ID) proteins/peptides are considered equally important for the protein functions. However, it is difficult to explore the structural features underlying the functions of ID proteins/peptides by conventional methods, such as X-ray crystallography, because of the flexibility of their secondary structures. Unlike voltage-gated potassium channels, families of small-and intermediate-conductance Ca 2+ -activated potassium (SK/IK) channels with important roles in regulating membrane excitability are activated exclusively by Ca 2+ -bound calmodulin (CaM). Upon binding of Ca 2+ to CaM, a 2 × 2 structure forms between CaM and the CaMbinding domain. A channel fragment that connects S6 and the CaMbinding domain is not visible in the protein crystal structure, suggesting that this fragment is an ID fragment. Here we show that the conformation of the ID fragment in SK channels becomes readily identifiable in the presence of NS309, the most potent compound that potentiates the channel activities. This well-defined conformation of the ID fragment, stabilized by NS309, increases the channel open probability at a given Ca 2+ concentration. Our results demonstrate that the ID fragment, itself a target for drugs modulating SK channel activities, plays a unique role in coupling Ca 2+ sensing by CaM and mechanical opening of SK channels.calcium | signaling | gating M ost proteins typically adopt one or more well-defined 3D structures, or domains, to carry out their specific functions. Voltage-gated potassium channels are such an example, with six transmembrane segments (S1-S6) forming the voltage-sensing domain and the pore domain (1, 2). Conformational changes of these domains result in opening of the channel pore. Unlike the well-structured proteins, there are proteins or fragments of proteins that lack well-defined 3D conformations (3-8). These proteins, termed "intrinsically disordered" (ID) proteins/peptides, typically are flexible in their secondary structures and often can adopt multiple conformations. Consequently, the structures of ID proteins are difficult to determine by conventional methods, such as X-ray crystallography, and it is difficult to explore the structural features responsible for functions by ID proteins. Nevertheless, emerging evidence shows that ID proteins/peptides are equally important for the protein functions.Small-and intermediate-conductance Ca 2+

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“…The voltage-insensitive calcium-activated K ϩ channel of intermediate conductance KCa3.1 is now emerging as a therapeutic target for a large variety of health disorders such as autoimmune diseases, vascular inflammation, and cancer (1)(2)(3)(4)(5)(6)(7). Increasing evidence also supports a prominent role of KCa3.1 in respiratory diseases such as allergic asthma (8) and airway obstruction coming from tissues remodeling (8,9).…”

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confidence: 99%

“…1 has not yet been solved. Knowledge of the channel key structural features is, however, essential for a molecular description of drug/channel interactions.…”

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confidence: 99%

Hydrophobic Interactions as Key Determinants to the KCa3.1 Channel Closed Configuration

Garneau¹,

Klein²,

Banderali³

et al. 2009

Journal of Biological Chemistry

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KCa3.1: target and marker for cancer, autoimmune disorder and vascular inflammation?

Cited by 74 publications

References 57 publications

Role of KCa3.1 Channels in Macrophage Polarization and Its Relevance in Atherosclerotic Plaque Instability

Role of KCa3.1 Channels in Macrophage Polarization and Its Relevance in Atherosclerotic Plaque Instability

Unstructured to structured transition of an intrinsically disordered protein peptide in coupling Ca ²⁺ -sensing and SK channel activation

Hydrophobic Interactions as Key Determinants to the KCa3.1 Channel Closed Configuration

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KCa3.1: target and marker for cancer, autoimmune disorder and vascular inflammation?

Cited by 74 publications

References 57 publications

Role of KCa3.1 Channels in Macrophage Polarization and Its Relevance in Atherosclerotic Plaque Instability

Role of KCa3.1 Channels in Macrophage Polarization and Its Relevance in Atherosclerotic Plaque Instability

Unstructured to structured transition of an intrinsically disordered protein peptide in coupling Ca 2+ -sensing and SK channel activation

Hydrophobic Interactions as Key Determinants to the KCa3.1 Channel Closed Configuration

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Unstructured to structured transition of an intrinsically disordered protein peptide in coupling Ca ²⁺ -sensing and SK channel activation