Next-generation inward rectifier potassium channel modulators: discovery and molecular pharmacology

Weaver, C. David; Denton, Jerod S.

doi:10.1152/ajpcell.00548.2020

Cited by 21 publications

(20 citation statements)

References 157 publications

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“…Our study highlights the GIRK channels as potentially important players in GNB1 Encephalopathy. Previous studies demonstrated strong links between malfunction or altered expression of neuronal GIRKs and epilepsy ( Jeremic et al., 2021 ; Luján et al., 2014 ; Lüscher and Slesinger, 2010 ) and GIRK openers have been found beneficial in treating several types of epilepsy in animal models ( Huang et al., 2018 ; Weaver and Denton, 2021 ; Wydeven et al., 2014 ; Zhao et al., 2020 ). Accordingly, the use of GIRK-directed therapies should be considered for treating the epileptic symptoms in GNB1 Encephalopathy.…”

Section: Discussionmentioning

confidence: 99%

Encephalopathy-causing mutations in Gβ1 (GNB1) alter regulation of neuronal GIRK channels

et al. 2021

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Summary Mutations in the GNB1 gene, encoding the Gβ 1 subunit of heterotrimeric G proteins, cause GNB1 Encephalopathy. Patients experience seizures, pointing to abnormal activity of ion channels or neurotransmitter receptors. We studied three Gβ 1 mutations (K78R, I80N and I80T) using computational and functional approaches. In heterologous expression models, these mutations did not alter the coupling between G protein-coupled receptors to G i/o , or the Gβγ regulation of the neuronal voltage-gated Ca 2+ channel Ca V 2.2. However, the mutations profoundly affected the Gβγ regulation of the G protein-gated inwardly rectifying potassium channels (GIRK, or Kir3). Changes were observed in Gβ 1 protein expression levels, Gβγ binding to cytosolic segments of GIRK subunits, and in Gβγ function, and included gain-of-function for K78R or loss-of-function for I80T/N, which were GIRK subunit-specific. Our findings offer new insights into subunit-dependent gating of GIRKs by Gβγ, and indicate diverse etiology of GNB1 Encephalopathy cases, bearing a potential for personalized treatment.

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Section: Discussionmentioning

confidence: 99%

Encephalopathy-causing mutations in Gβ1 (GNB1) alter regulation of neuronal GIRK channels

et al. 2021

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“…To examine whether the ROMK protein acts as a possible mitoK ATP channel-forming component, research has focused on the use of compounds regulating the activity of this protein. For example, it was reported that VU591 inhibits ROMK channels with high specificity [ 62 , 63 , 64 ]. However, this molecule induced mitochondrial depolarization and matrix contraction in mitochondria from both wild-type and ROMK knockout cells.…”

Section: Modulators Of Mitochondrial Atp-sensitive Potassium Channelsmentioning

confidence: 99%

Alternative Targets for Modulators of Mitochondrial Potassium Channels

et al. 2022

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Mitochondrial potassium channels control potassium influx into the mitochondrial matrix and thus regulate mitochondrial membrane potential, volume, respiration, and synthesis of reactive oxygen species (ROS). It has been found that pharmacological activation of mitochondrial potassium channels during ischemia/reperfusion (I/R) injury activates cytoprotective mechanisms resulting in increased cell survival. In cancer cells, the inhibition of these channels leads to increased cell death. Therefore, mitochondrial potassium channels are intriguing targets for the development of new pharmacological strategies. In most cases, however, the substances that modulate the mitochondrial potassium channels have a few alternative targets in the cell. This may result in unexpected or unwanted effects induced by these compounds. In our review, we briefly present the various classes of mitochondrial potassium (mitoK) channels and describe the chemical compounds that modulate their activity. We also describe examples of the multidirectional activity of the activators and inhibitors of mitochondrial potassium channels.

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“…Currently, the activation of neuronal GIRK channels, specifically GIRK1/2, is considered a promising pharmaceutical strategy against many neurological and psychiatric conditions, such as epilepsy, hyperalgesia, and neurodegenerative diseases [1,3,5,6]. In this article, we report the identification of AsKC11, a Kunitz toxin/peptide found in Anemonia sulcata, that activates GIRK channels.…”

Section: Discussionmentioning

confidence: 98%

“…Moreover, several studies have shown the functions of GIRK channels in pathological conditions. Pharmacologically increasing the activity of GIRK channels can induce efficacy in rodent models of numerous neurological or psychiatric disorders, for instance, antiseizure, anxiolytic, antinociceptive, and rescue of amyloid-βevoked deficits in hippocampal function [2,3,[11][12][13][14][15][16][17][18]. These studies suggest the therapeutic potential of activating neuronal GIRK channels, especially the primary GIRK1/2, to treat brain diseases in humans [5].…”

Section: Introductionmentioning

confidence: 97%

“…G protein-coupled inward-rectifier potassium (GIRK/Kir3) channels are members of a large family of inward-rectifying potassium (Kir1-7) channels, which have been studied intensively for nearly three decades [1][2][3]. GIRK channels exist as tetrameric complexes comprising either identical (homomeric) or similar (heteromeric) subunits that encode a K + selectivity-filter-containing transmembrane pore (TMD for transmembrane domain) serving to conduct potassium ions and a cytoplasmic domain (CTD) [3,4]. The TMD and CTD are covalently linked by a tether, called the TMD-CTD linker [4].…”

Section: Introductionmentioning

confidence: 99%

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AsKC11, a Kunitz Peptide from Anemonia sulcata, Is a Novel Activator of G Protein-Coupled Inward-Rectifier Potassium Channels

Pinheiro-Júnior

Béress

et al. 2022

Marine Drugs

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(1) Background: G protein-coupled inward-rectifier potassium (GIRK) channels, especially neuronal GIRK1/2 channels, have been the focus of intense research interest for developing drugs against brain diseases. In this context, venom peptides that selectively activate GIRK channels can be seen as a new source for drug development. Here, we report on the identification and electrophysiological characterization of a novel activator of GIRK1/2 channels, AsKC11, found in the venom of the sea anemone Anemonia sulcata. (2) Methods: AsKC11 was purified from the sea anemone venom by reverse-phase chromatography and the sequence was identified by mass spectrometry. Using the two-electrode voltage-clamp technique, the activity of AsKC11 on GIRK1/2 channels was studied and its selectivity for other potassium channels was investigated. (3) Results: AsKC11, a Kunitz peptide found in the venom of A. sulcata, is the first peptide shown to directly activate neuronal GIRK1/2 channels independent from Gi/o protein activity, without affecting the inward-rectifier potassium channel (IRK1) and with only a minor effect on KV1.6 channels. Thus, AsKC11 is a novel activator of GIRK channels resulting in larger K+ currents because of an increased chord conductance. (4) Conclusions: These discoveries provide new insights into a novel class of GIRK activators.

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Next-generation inward rectifier potassium channel modulators: discovery and molecular pharmacology

Cited by 21 publications

References 157 publications

Encephalopathy-causing mutations in Gβ1 (GNB1) alter regulation of neuronal GIRK channels

Encephalopathy-causing mutations in Gβ1 (GNB1) alter regulation of neuronal GIRK channels

Alternative Targets for Modulators of Mitochondrial Potassium Channels

AsKC11, a Kunitz Peptide from Anemonia sulcata, Is a Novel Activator of G Protein-Coupled Inward-Rectifier Potassium Channels

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