Cardiac and renal inward rectifier potassium channel pharmacology: emerging tools for integrative physiology and therapeutics

Swale, Daniel R.; Kharade, Sujay V.; Denton, Jerod S.

doi:10.1016/j.coph.2013.11.002

Cited by 22 publications

(26 citation statements)

References 56 publications

(67 reference statements)

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“…Kir channels play critical roles in the regulation of multiple cellular functions including repolarization of action potentials, K + homeostasis and hormone secretion (Hibino et al, 2010; Swale et al, 2014). Among the Kir family, the Kir4.1 subunit is predominantly expressed in brain astrocytes mediating, at least partly, the astroglial spatial K + buffering (Neusch et al, 2006; Kucheryavyk et al, 2007).…”

Section: Introductionmentioning

confidence: 99%

Inhibition of Kir4.1 potassium channels by quinacrine

et al. 2017

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Inwardly rectifying potassium (Kir) channels are expressed in many cell types and contribute to a wide range of physiological processes. Particularly, Kir4.1 channels are involved in the astroglial spatial potassium buffering. In this work, we examined the effects of the cationic amphiphilic drug quinacrine on Kir4.1 channels heterologously expressed in HEK293 cells, employing the patch clamp technique. Quinacrine inhibited the currents of Kir4.1 channels in a concentration and voltage dependent manner. In inside-out patches, quinacrine inhibited Kir4.1 channels with an IC50 value of 1.8 ± 0.3 μM and with extremely slow blocking and unblocking kinetics. Molecular modeling combined with mutagenesis studies suggested that quinacrine blocks Kir4.1 by plugging the central cavity of the channels, stabilized by the residues E158 and T128. Overall, this study shows that quinacrine blocks Kir4.1 channels, which would be expected to impact the potassium transport in several tissues.

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Section: Introductionmentioning

confidence: 99%

Inhibition of Kir4.1 potassium channels by quinacrine

et al. 2017

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“…These channels occur both in the CNS and peripheral organs, including the heart, kidney and lungs; they play major roles in normal physiologic processes and contribute to pathologies as diverse as cancer and diabetes (see 88,95,317,319,481,528,548,554 for reviews of K + channels in the brain). Under most conditions, opening of these channels results in an increased flow of K + ions out of the cell and, consequently, a shift toward a more hyperpolarized membrane potential.…”

Section: Neurotransmitters and Peptides Exerting State-dependent Contmentioning

confidence: 99%

Neural Control of the Upper Airway: Respiratory and State‐Dependent Mechanisms

Kubin

2016

Comprehensive Physiology

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Upper airway muscles subserve many essential for survival orofacial behaviors, including their important role as accessory respiratory muscles. In the face of certain predisposition of craniofacial anatomy, both tonic and phasic inspiratory activation of upper airway muscles is necessary to protect the upper airway against collapse. This protective action is adequate during wakefulness, but fails during sleep which results in recurrent episodes of hypopneas and apneas, a condition known as the obstructive sleep apnea syndrome (OSA). Although OSA is almost exclusively a human disorder, animal models help unveil the basic principles governing the impact of sleep on breathing and upper airway muscle activity. This article discusses the neuroanatomy, neurochemistry, and neurophysiology of the different neuronal systems whose activity changes with sleep-wake states, such as the noradrenergic, serotonergic, cholinergic, orexinergic, histaminergic, GABAergic and glycinergic, and their impact on central respiratory neurons and upper airway motoneurons. Observations of the interactions between sleep-wake states and upper airway muscles in healthy humans and OSA patients are related to findings from animal models with normal upper airway, and various animal models of OSA, including the chronic-intermittent hypoxia model. Using a framework of upper airway motoneurons being under concurrent influence of central respiratory, reflex and state-dependent inputs, different neurotransmitters, and neuropeptides are considered as either causing a sleep-dependent withdrawal of excitation from motoneurons or mediating an active, sleep-related inhibition of motoneurons. Information about the neurochemistry of state-dependent control of upper airway muscles accumulated to date reveals fundamental principles and may help understand and treat OSA.

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“…Inward rectifier potassium (Kir) channels play fundamental roles in diverse organ systems, and could in some cases represent unexploited drug targets for neurological, cardiovascular, endocrine, and muscle disorders 1, 2 . Kir7.1, which is encoded by KCNJ13 , one of sixteen genes comprising the Kir channel family, is expressed in the eye, brain, uterus, kidney, gut, and thyroid gland 3–9 .…”

Section: Introductionmentioning

confidence: 99%

ML418: The First Selective, Sub-Micromolar Pore Blocker of Kir7.1 Potassium Channels

Swale¹,

Kurata²,

Kharade³

et al. 2016

ACS Chem. Neurosci.

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The inward rectifier potassium (Kir) channel Kir7.1 (KCNJ13) has recently emerged as a key regulator of melanocortin signaling in the brain, electrolyte homeostasis in the eye, and uterine muscle contractility during pregnancy. The pharmacological tools available for exploring the physiology and therapeutic potential of Kir7.1 have been limited to relatively weak and nonselective small-molecule inhibitors. Here, we report the discovery in a fluorescence-based highthroughput screen of a novel Kir7.1 channel inhibitor, VU714. Site-directed mutagenesis of porelining amino acid residues identified Glutamate 149 and Alanine 150 as essential determinants of VU714 activity. Lead optimization with medicinal chemistry generated ML418, which exhibits sub-micromolar activity (IC 50 = 310 nM) and superior selectivity over other Kir channels (at least 17-fold selective over Kir1.1, Kir2.1, Kir2.2, Kir2.3, Kir3.1/3.2, and Kir4.1) except for Kir6.2/ SUR1 (equally potent). Evaluation in the EuroFins Lead Profiling panel of 64 GPCRs, ionchannels and transporters for off-target activity of ML418 revealed a relatively clean ancillary pharmacology. While ML418 exhibited low CL HEP in human microsomes which could be modulated with lipophilicity adjustments, it showed high CL HEP in rat microsomes regardless of lipophilicity. A subsequent in vivo PK study of ML418 by intraperitoneal (IP) administration (30 mg/kg dosage) revealed a suitable PK profile (C max = 0.20 µM and T max = 3 hours) and favorable CNS distribution (mouse brain:plasma K p of 10.9 to support in vivo studies for in vivo studies.

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Cardiac and renal inward rectifier potassium channel pharmacology: emerging tools for integrative physiology and therapeutics

Cited by 22 publications

References 56 publications

Inhibition of Kir4.1 potassium channels by quinacrine

Inhibition of Kir4.1 potassium channels by quinacrine

Neural Control of the Upper Airway: Respiratory and State‐Dependent Mechanisms

ML418: The First Selective, Sub-Micromolar Pore Blocker of Kir7.1 Potassium Channels

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