Screening Technologies for Inward Rectifier Potassium Channels: Discovery of New Blockers and Activators

Walsh, Kenneth B.

doi:10.1177/2472555220905558

Cited by 15 publications

(13 citation statements)

References 104 publications

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“…For example, voltage-regulated potassium channels offer opportunities for the development of new drugs for cancer, autoimmune diseases; and metabolic, neurological, and cardiovascular disorders [4][5][6][7]. Clinically used potassium channel modulators comprise of hypoglycemic sulfonylureas (potassium channel blockers, such as glibenclamide), antiarrhythmic agents (nonselective potassium channel blockers, such as dexsotalol or nifekalant), antianginal and cardioprotective agents (potassium channel openers, such as nicorandil or levosimendan), and anticonvulsants (potassium channel openers, such as retigabine) [8].…”

Section: Introductionmentioning

confidence: 99%

Mitochondrial Potassium Channels as Druggable Targets

et al. 2020

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Mitochondrial potassium channels have been described as important factors in cell pro-life and death phenomena. The activation of mitochondrial potassium channels, such as ATP-regulated or calcium-activated large conductance potassium channels, may have cytoprotective effects in cardiac or neuronal tissue. It has also been shown that inhibition of the mitochondrial Kv1.3 channel may lead to cancer cell death. Hence, in this paper, we examine the concept of the druggability of mitochondrial potassium channels. To what extent are mitochondrial potassium channels an important, novel, and promising drug target in various organs and tissues? The druggability of mitochondrial potassium channels will be discussed within the context of channel molecular identity, the specificity of potassium channel openers and inhibitors, and the unique regulatory properties of mitochondrial potassium channels. Future prospects of the druggability concept of mitochondrial potassium channels will be evaluated in this paper.

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Section: Introductionmentioning

confidence: 99%

Mitochondrial Potassium Channels as Druggable Targets

et al. 2020

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“…The Kir channel opener flecainide, an antiarrhythmic drug, increases Kir2.1 currents by binding to cysteine 311 and reducing polyamine-induced rectification [ 167 ]. To our knowledge, this drug is a unique drug that can activate Kir 2.1. channels [ 168 ]. Moreover, the ion Mg 2+ was proposed as an activator of Kir channels in vascular SMCs [ 1 ].…”

Section: Clinical Importance and Medical Uses Of K + mentioning

confidence: 99%

“…In contrast, several drugs are proposed as blockers of Kir channels, namely, the antimalarial drug chloroquine [ 169 , 170 ], the antiarrhythmic drug quinidine [ 167 ], the diamine pentamidine analog 6 (PA-6) [ 171 ], and a more recent prototype of Kir blocker, ML133 [ 172 ]. Moreover, these channels are markedly sensitive to inorganic cations (e.g., Ba 2+ and Cs + ) but are insensitive to 4-AP [ 168 ]. Although the presence of Kir channels in HUA is uncertain, the next pharmacological studies focusing on the development of new targets for Kir2.1 channels can be the first promising step at the vascular level.…”

Section: Clinical Importance and Medical Uses Of K + mentioning

confidence: 99%

Clinical Importance of the Human Umbilical Artery Potassium Channels

Lorigo

Oliveira

2020

Cells

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Potassium (K+) channels are usually predominant in the membranes of vascular smooth muscle cells (SMCs). These channels play an important role in regulating the membrane potential and vessel contractility—a role that depends on the vascular bed. Thus, the activity of K+ channels represents one of the main mechanisms regulating the vascular tone in physiological and pathophysiological conditions. Briefly, the activation of K+ channels in SMC leads to hyperpolarization and vasorelaxation, while its inhibition induces depolarization and consequent vascular contraction. Currently, there are four different types of K+ channels described in SMCs: voltage-dependent K+ (KV) channels, calcium-activated K+ (KCa) channels, inward rectifier K+ (Kir) channels, and 2-pore domain K+ (K2P) channels. Due to the fundamental role of K+ channels in excitable cells, these channels are promising therapeutic targets in clinical practice. Therefore, this review discusses the basic properties of the various types of K+ channels, including structure, cellular mechanisms that regulate their activity, and new advances in the development of activators and blockers of these channels. The vascular functions of these channels will be discussed with a focus on vascular SMCs of the human umbilical artery. Then, the clinical importance of K+ channels in the treatment and prevention of cardiovascular diseases during pregnancy, such as gestational hypertension and preeclampsia, will be explored.

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“…These observations indicate the potential for isoform-specific K ir 2.x activating compound development by targeting this channel domain but also indicate that other regions of the channel protein should be targeted for the development of multi-isoform activators. Furthermore, high throughput screening methods, such as automated patch-clamp, optical membrane potential detection, and ion-flux measurements, are being developed that will further aid the generation of AgoKirs [66].…”

Section: Lead Compounds and Clinical Perspectivementioning

confidence: 99%

Towards the Development of AgoKirs: New Pharmacological Activators to Study Kir2.x Channel and Target Cardiac Disease

Schoor

Hattum

Wilde

et al. 2020

IJMS

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Inward rectifier potassium ion channels (IK1-channels) of the Kir2.x family are responsible for maintaining a stable negative resting membrane potential in excitable cells, but also play a role in processes of non-excitable tissues, such as bone development. IK1-channel loss-of-function, either congenital or acquired, has been associated with cardiac disease. Currently, basic research and specific treatment are hindered by the absence of specific and efficient Kir2.x channel activators. However, twelve different compounds, including approved drugs, show off-target IK1 activation. Therefore, these compounds contain valuable information towards the development of agonists of Kir channels, AgoKirs. We reviewed the mechanism of IK1 channel activation of these compounds, which can be classified as direct or indirect activators. Subsequently, we examined the most viable starting points for rationalized drug development and possible safety concerns with emphasis on cardiac and skeletal muscle adverse effects of AgoKirs. Finally, the potential value of AgoKirs is discussed in view of the current clinical applications of potentiators and activators in cystic fibrosis therapy.

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Screening Technologies for Inward Rectifier Potassium Channels: Discovery of New Blockers and Activators

Cited by 15 publications

References 104 publications

Mitochondrial Potassium Channels as Druggable Targets

Mitochondrial Potassium Channels as Druggable Targets

Clinical Importance of the Human Umbilical Artery Potassium Channels

Towards the Development of AgoKirs: New Pharmacological Activators to Study Kir2.x Channel and Target Cardiac Disease

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