Chemical modulation of Kv7 potassium channels

Borgini, Matteo; Mondal, Pravat; Liu, Ruiting; Wipf, Peter

doi:10.1039/d0md00328j

Cited by 21 publications

(12 citation statements)

References 377 publications

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“…A great deal of attention has been focused on achieving rescue of Kv7 channel function across the numerous pathogenic variants found in Kv7.2 or Kv7.3 subunits. A number of Kv7 activators have been reported that could provide potential recovery of function in Kv7.2 mutations ( Borgini et al., 2021 ; Incontro et al., 2021 ; Kanyo et al., 2020 ; Larsson et al., 2020b ; Vanoye et al., 2022 ), although non-specific actions or side effects have led to removal of some of these drugs from clinical use ( Brickel et al., 2020 ). The proband with Kv7.2H260del had resolution of seizures through use of CBD:THC oil.…”

Section: Discussionmentioning

confidence: 99%

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Cannabidiol counters the effects of a dominant-negative pathogenic Kv7.2 variant

Zhan¹,

Drummond-Main²,

Greening³

et al. 2022

iScience

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Section: Discussionmentioning

confidence: 99%

“…However, it is possible that CBD could interact with other receptors or channels in tsA-201 cells that could invoke other factors that modulate Kv7 channels (i.e. PiP2, PKC, calmodulin, arachidonic acid, and ERK1-2) ( Borgini et al., 2021 ; Greene and Hoshi, 2016 ; Hudson et al., 2019 ; Larsson et al., 2020a ).…”

Section: Discussionmentioning

confidence: 99%

Cannabidiol counters the effects of a dominant-negative pathogenic Kv7.2 variant

Zhan¹,

Drummond-Main²,

Greening³

et al. 2022

iScience

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“…Activated PKC phosphorylates the C-terminus in the calmodulin (CaM) binding site of the Kv7.2 subunit assisted by A-kinase-anchoring protein AKAP79/150. The phosphorylated state of the channel destabilizes the Kv7 channel/PIP 2 complex and consequently PIP 2 hydrolysis suppresses the M-current [80][81][82][83].…”

Section: Discussionmentioning

confidence: 99%

Antagonism of the Muscarinic Acetylcholine Type 1 Receptor Enhances Mitochondrial Membrane Potential and Expression of Respiratory Chain Components via AMPK in Human Neuroblastoma SH-SY5Y Cells and Primary Neurons

2022

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Impairments in mitochondrial physiology play a role in the progression of multiple neurodegenerative conditions, including peripheral neuropathy in diabetes. Blockade of muscarinic acetylcholine type 1 receptor (M1R) with specific/selective antagonists prevented mitochondrial dysfunction and reversed nerve degeneration in in vitro and in vivo models of peripheral neuropathy. Specifically, in type 1 and type 2 models of diabetes, inhibition of M1R using pirenzepine or muscarinic toxin 7 (MT7) induced AMP-activated protein kinase (AMPK) activity in dorsal root ganglia (DRG) and prevented sensory abnormalities and distal nerve fiber loss. The human neuroblastoma SH-SY5Y cell line has been extensively used as an in vitro model system to study mechanisms of neurodegeneration in DRG neurons and other neuronal sub-types. Here, we tested the hypothesis that pirenzepine or MT7 enhance AMPK activity and via this pathway augment mitochondrial function in SH-SY5Y cells. M1R expression was confirmed by utilizing a fluorescent dye, ATTO590-labeled MT7, that exhibits great specificity for this receptor. M1R antagonist treatment in SH-SY5Y culture increased AMPK phosphorylation and mitochondrial protein expression (OXPHOS). Mitochondrial membrane potential (MMP) was augmented in pirenzepine and MT7 treated cultured SH-SY5Y cells and DRG neurons. Compound C or AMPK-specific siRNA suppressed pirenzepine or MT7-induced elevation of OXPHOS expression and MMP. Moreover, muscarinic antagonists induced hyperpolarization by activating the M-current and, thus, suppressed neuronal excitability. These results reveal that negative regulation of this M1R-dependent pathway could represent a potential therapeutic target to elevate AMPK activity, enhance mitochondrial function, suppress neuropathic pain, and enhance nerve repair in peripheral neuropathy.

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“…The morphological formation of these neurons within the hippocampus leads to the further subfield classification of pyramidal cells in what is known as Cornu Ammonus (CA), divided into CA1, CA2, and CA3 [ 49 , 50 ]. These regions serve an important role in localizing KCNQ channel function in synaptic plasticity [ 49 , 51 , 52 , 53 , 54 , 55 , 56 , 57 , 58 , 59 , 60 , 61 ]. Within synaptic plasticity, two major models involved in the application of neural plasticity are long-term potentiation (LTP) and long-term depression (LTD) [ 59 ].…”

Section: Modulation Of Synaptic Plasticity By Kcnq Channelsmentioning

confidence: 99%

“…This plays a key role in maintaining the K + gradient for channel mechanosensation to carry K + into hair cells to stimulate auditory sensation [ 14 , 38 ]. KCNQ4 mutations are often associated with auditory hearing loss and have therefore been a key target in developing pharmacotherapeutic options for hearing loss [ 39 , 40 , 41 , 42 , 43 , 44 , 45 , 46 , 47 , 48 , 49 , 50 , 51 , 52 , 53 , 54 ]. KCNQ5 is most expressed in neural tissue, including the retinal pigment epithelium [ 48 ].…”

Section: Introductionmentioning

confidence: 99%

Behavior of KCNQ Channels in Neural Plasticity and Motor Disorders

et al. 2022

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The broad distribution of voltage-gated potassium channels (VGKCs) in the human body makes them a critical component for the study of physiological and pathological function. Within the KCNQ family of VGKCs, these aqueous conduits serve an array of critical roles in homeostasis, especially in neural tissue. Moreover, the greater emphasis on genomic identification in the past century has led to a growth in literature on the role of the ion channels in pathological disease as well. Despite this, there is a need to consolidate the updated findings regarding both the pharmacotherapeutic and pathological roles of KCNQ channels, especially regarding neural plasticity and motor disorders which have the largest body of literature on this channel. Specifically, KCNQ channels serve a remarkable role in modulating the synaptic efficiency required to create appropriate plasticity in the brain. This role can serve as a foundation for clinical approaches to chronic pain. Additionally, KCNQ channels in motor disorders have been utilized as a direction for contemporary pharmacotherapeutic developments due to the muscarinic properties of this channel. The aim of this study is to provide a contemporary review of the behavior of these channels in neural plasticity and motor disorders. Upon review, the behavior of these channels is largely dependent on the physiological role that KCNQ modulatory factors (i.e., pharmacotherapeutic options) serve in pathological diseases.

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Chemical modulation of Kv7 potassium channels

Abstract: This review describes the synthetic and medicinal chemistry of small molecule modulators of the voltage-gated Kv7 (KCNQ) potassium channels and the available data of their biological and clinical properties.

Cited by 21 publications

References 377 publications

Cannabidiol counters the effects of a dominant-negative pathogenic Kv7.2 variant

Cannabidiol counters the effects of a dominant-negative pathogenic Kv7.2 variant

Antagonism of the Muscarinic Acetylcholine Type 1 Receptor Enhances Mitochondrial Membrane Potential and Expression of Respiratory Chain Components via AMPK in Human Neuroblastoma SH-SY5Y Cells and Primary Neurons

Behavior of KCNQ Channels in Neural Plasticity and Motor Disorders

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