Calcium ion channels: challenges and successes in drug discovery

McDonough, Stefan I.

doi:10.1002/wmts.71

Cited by 4 publications

(3 citation statements)

References 170 publications

(171 reference statements)

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“…Consistent with this hypothesis, a clinical trial using a γ-aminobutyric acid type B (GABA B ) agonist (R-baclofen), an inhibitory modulator of N-type calcium channels 47 , found some improvement of social function and behaviour in FXS patients 48 . Our study opens the possibility that small molecule inhibitors of Ca V 2.2, currently being developed for a number of chronic pain conditions 49 , could be of benefit in FXS.…”

Section: Discussionmentioning

confidence: 84%

Fragile X mental retardation protein controls synaptic vesicle exocytosis by modulating N-type calcium channel density

et al. 2014

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Fragile X syndrome (FXS), the most common heritable form of mental retardation, is characterized by synaptic dysfunction. Synaptic transmission depends critically on presynaptic calcium entry via voltage-gated calcium (CaV) channels. Here we show that the functional expression of neuronal N-type CaV channels (CaV2.2) is regulated by fragile X mental retardation protein (FMRP). We find that FMRP knockdown in dorsal root ganglion neurons increases CaV channel density in somata and in presynaptic terminals. We then show that FMRP controls CaV2.2 surface expression by targeting the channels to the proteasome for degradation. The interaction between FMRP and CaV2.2 occurs between the carboxy-terminal domain of FMRP and domains of CaV2.2 known to interact with the neurotransmitter release machinery. Finally, we show that FMRP controls synaptic exocytosis via CaV2.2 channels. Our data indicate that FMRP is a potent regulator of presynaptic activity, and its loss is likely to contribute to synaptic dysfunction in FXS.

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Section: Discussionmentioning

confidence: 84%

Fragile X mental retardation protein controls synaptic vesicle exocytosis by modulating N-type calcium channel density

et al. 2014

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“…Considering the functionality of TRP ion channels, an increase in intracellular Ca 2+ concentration in response to stimuli is a good indicator of these channels’ functional expression ( Zheng, 2013 ). Calcium channels control not only disease-related functions but also important physiological functions throughout the body that might be perilous if interrupted ( McDonough, 2013 ). Many of these channels have unknown mechanisms of action.…”

Section: Application Of Ion Channel Technology For the Study Of Trp C...mentioning

confidence: 99%

A Review on the Role of TRP Channels and Their Potential as Drug Targets_An Insight Into the TRP Channel Drug Discovery Methodologies

Fallah¹,

Ahuja²,

Lin³

et al. 2022

Front. Pharmacol.

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Transient receptor potential (TRP) proteins are a large group of ion channels that control many physiological functions in our body. These channels are considered potential therapeutic drug targets for various diseases such as neurological disorders, cancers, cardiovascular disease, and many more. The Nobel Prize in Physiology/Medicine in the year 2021 was awarded to two scientists for the discovery of TRP and PIEZO ion channels. Improving our knowledge of technologies for their study is essential. In the present study, we reviewed the role of TRP channel types in the control of normal physiological functions as well as disease conditions. Also, we discussed the current and novel technologies that can be used to study these channels successfully. As such, Flux assays for detecting ionic flux through ion channels are among the core and widely used tools for screening drug compounds. Technologies based on these assays are available in fully automated high throughput set-ups and help detect changes in radiolabeled or non-radiolabeled ionic flux. Aurora’s Ion Channel Reader (ICR), which works based on label-free technology of flux assay, offers sensitive, accurate, and reproducible measurements to perform drug ranking matching with patch-clamp (gold standard) data. The non-radiolabeled trace-based flux assay coupled with the ICR detects changes in various ion types, including potassium, calcium, sodium, and chloride channels, by using appropriate tracer ions. This technology is now considered one of the very successful approaches for analyzing ion channel activity in modern drug discovery. It could be a successful approach for studying various ion channels and transporters, including the different members of the TRP family of ion channels.

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“…Both the physiological and pathophysiological roles of Ca 2+ signaling proteins highlight their clinical relevance. Although there are cases where Ca 2+ pharmacology turned out to be successful in therapy [ 14 , 15 ], Ca 2+ ion channels are unfortunately still technically difficult in regard to target-specific drug discovery [ 16 , 17 , 18 ]. A detailed understanding of the structure–function relationship of essential Ca 2+ signaling proteins and associated downstream signaling events is fundamental for the development of well-directed therapeutic approaches.…”

Section: Introductionmentioning

confidence: 99%

Deciphering Molecular Mechanisms and Intervening in Physiological and Pathophysiological Processes of Ca2+ Signaling Mechanisms Using Optogenetic Tools

Maltan

Najjar

Tiffner

et al. 2021

Cells

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Calcium ion channels are involved in numerous biological functions such as lymphocyte activation, muscle contraction, neurotransmission, excitation, hormone secretion, gene expression, cell migration, memory, and aging. Therefore, their dysfunction can lead to a wide range of cellular abnormalities and, subsequently, to diseases. To date various conventional techniques have provided valuable insights into the roles of Ca2+ signaling. However, their limited spatiotemporal resolution and lack of reversibility pose significant obstacles in the detailed understanding of the structure–function relationship of ion channels. These drawbacks could be partially overcome by the use of optogenetics, which allows for the remote and well-defined manipulation of Ca2+-signaling. Here, we review the various optogenetic tools that have been used to achieve precise control over different Ca2+-permeable ion channels and receptors and associated downstream signaling cascades. We highlight the achievements of optogenetics as well as the still-open questions regarding the resolution of ion channel working mechanisms. In addition, we summarize the successes of optogenetics in manipulating many Ca2+-dependent biological processes both in vitro and in vivo. In summary, optogenetics has significantly advanced our understanding of Ca2+ signaling proteins and the used tools provide an essential basis for potential future therapeutic application.

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Calcium ion channels: challenges and successes in drug discovery

Cited by 4 publications

References 170 publications

Fragile X mental retardation protein controls synaptic vesicle exocytosis by modulating N-type calcium channel density

Fragile X mental retardation protein controls synaptic vesicle exocytosis by modulating N-type calcium channel density

A Review on the Role of TRP Channels and Their Potential as Drug Targets_An Insight Into the TRP Channel Drug Discovery Methodologies

Deciphering Molecular Mechanisms and Intervening in Physiological and Pathophysiological Processes of Ca2+ Signaling Mechanisms Using Optogenetic Tools

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