Benzothiazepine CGP37157 and its 2′-isopropyl analogue modulate Ca2+ entry through CALHM1

Moreno-Ortega, Ana J.; Martínez-Sanz, Francisco J.; Lajarín-Cuesta, Rocío; Rı́os, Cristóbal de los; Cano‐Abad, María F.

doi:10.1016/j.neuropharm.2015.02.016

Cited by 22 publications

(38 citation statements)

References 28 publications

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“…As mentioned above, previous findings from our laboratory [21] demonstrated that CGP37157 modulated massive Ca 2+ entry through CALHM1 by blocking it. Due to the properties of CGP37157, new experiments were performed in Calhm1 +/+ , Calhm1 +/− , and Calhm1 −/− mice hippocampal slices exposed to OGD/Reox in the presence or absence of CGP37157 at 10 µM.…”

Section: Cgp37157 Requires Calhm1 To Exert Neuroprotection Under Ogd/supporting

confidence: 61%

“…As previously described in our laboratory [21], CGP37157 reduces Ca 2+ influx through CALHM1 in Hela cells. Hela cells lack L-type VDCCs, and when transiently transfected with CALHM1, the only Ca 2+ -permeant channel expressed in the plasma membrane is CALHM1.…”

Section: Genetic Ablation Of Calhm1 Promotes Neuroprotection In the Gsupporting

confidence: 59%

“…Also, its pharmacological blockade with Ruthenium Red (RuRed) or its silencing by using short hairpin RNA specific for CALHM1 (sh-CALHM1) induces neuroprotection in cultured cortical neurons subjected to oxygen and glucose deprivation (OGD) [20]. However, the molecular mechanisms underlying this neuroprotective process is still unknown.The benzothiazepine CGP37157 was the first organic compound shown to have the ability to modulate the Ca 2+ influx through CALHM1; at 1 µM, it reduces by over 50% the [Ca 2+ ] i after the removal and following the add-back of Ca 2+ (conditions by which CALHM1 is activated) in Hela cells overexpressing CALHM1 [21]. Alternatively, CGP37157 is recognized as a blocker of the Na + /Ca 2+ Cells 2020, 9, 664 3 of 13…”

mentioning

confidence: 99%

“…The benzothiazepine CGP37157 was the first organic compound shown to have the ability to modulate the Ca 2+ influx through CALHM1; at 1 µM, it reduces by over 50% the [Ca 2+ ] i after the removal and following the add-back of Ca 2+ (conditions by which CALHM1 is activated) in Hela cells overexpressing CALHM1 [21]. Alternatively, CGP37157 is recognized as a blocker of the Na + /Ca 2+ Cells 2020, 9, 664 3 of 13…”

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confidence: 99%

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Molecular and Pharmacological Modulation of CALHM1 Promote Neuroprotection against Oxygen and Glucose Deprivation in a Model of Hippocampal Slices

Garrosa

Paredes

Marambaud

et al. 2020

Cells

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Calcium homeostasis modulator 1 (CALHM1) is a calcium channel involved in the regulation of cytosolic Ca 2+ levels. From a physiological point of view, the open state of CALHM1 depends not only on voltage but also on the extracellular concentration of calcium ([Ca 2+ ]) ions. At low [Ca 2+ ] e or depolarization, the channel is opened, allowing Ca 2+ influx; however, high extracellular [Ca 2+ ] e or hyperpolarization promote its resting state. The unique Ca 2+ permeation of CALHM1 relates to the molecular events that take place in brain ischemia, such as depolarization and extracellular changes in [Ca 2+ ] e , particularly during the reperfusion phase after the ischemic insult. In this study, we attempted to understand its role in an in vitro model of ischemia, namely oxygen and glucose deprivation, followed by reoxygenation (OGD/Reox). To this end, hippocampal slices from wild-type Calhm1 +/+ , Calhm1 +/− , and Calhm1 −/− mice were subjected to OGD/Reox. Our results point out to a neuroprotective effect when CALHM1 is partially or totally absent. Pharmacological manipulation of CALHM1 with CGP37157 reduced cell death in Calhm1 +/+ slices but not in that of Calhm1 −/− mice after exposure to the OGD/Reox protocol. This ionic protection was also verified by measuring reactive oxygen species production upon OGD/Reox in Calhm1 +/+ and Calhm1 −/− mice, resulting in a downregulation of ROS production in Calhm1 −/− hippocampal slices and increased expression of HIF-1α. Taken together, we can conclude that genetic or pharmacological inhibition of CALHM1 results in a neuroprotective effect against ischemia, due to an attenuation of the neuronal calcium overload and downregulation of oxygen reactive species production.Cells 2020, 9, 664 2 of 13 plasminogen activator (rt-PA), has limitations [3][4][5]. During ischemic stroke, the acute occlusion of a vessel produces a rapid central core of brain infarct tissue where cells suffer necrosis. This core area is surrounded by a hypoxic but potentially salvageable tissue-the ischemic penumbra, where the blood flow reduction is not so drastic [6].The drop in blood flow triggers a decrease of oxygen and glucose supply in the infarct area, promoting a disruption in the electron transport chain that leads to mitochondrial failure and a reduction of ATP levels. This decrease in ATP induces the malfunctioning of different membrane pumps such as Na + /K + /ATPase and Ca 2+ /ATPase, promoting membrane depolarization due to Na + influx. This depolarization provokes the opening of voltage-dependent calcium channels (VDCCs) and makes the Na + /Ca 2+ exchanger work in its reverse way; these two processes lead to intracellular Ca 2+ overload [7,8]. This massive entry of Ca 2+ into the neurons induces glutamate excitotoxicity, triggers the production of reactive oxygen species (ROS), and the release of inflammatory cytokines that ultimately lead to neuronal death [9][10][11][12]. Therefore, maintenance of intracellular Ca 2+ homeostasis is crucial for cellular survival and function [11].Consider...

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Section: Cgp37157 Requires Calhm1 To Exert Neuroprotection Under Ogd/supporting

confidence: 61%

Section: Genetic Ablation Of Calhm1 Promotes Neuroprotection In the Gsupporting

confidence: 59%

mentioning

confidence: 99%

mentioning

confidence: 99%

See 2 more Smart Citations

Molecular and Pharmacological Modulation of CALHM1 Promote Neuroprotection against Oxygen and Glucose Deprivation in a Model of Hippocampal Slices

Garrosa

Paredes

Marambaud

et al. 2020

Cells

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“…It has also been shown to form a novel Ca 2+ ‐permeable ion channel, whose gating is allosterically regulated by both membrane voltage and extracellular Ca 2+ concentration; in addition, CALHM1 is insensitive to classic selective blockers of voltage‐gated Ca 2+ channels, although it is inhibited by nonselective and inorganic Ca 2+ channel blockers such as Co 2+ (Dreses‐Werringloer et al ., 2008; Moreno‐Ortega et al ., 2010; Ma et al ., 2012). But recently we described that CAHM1 is blocked by CGP37157 (Moreno‐Ortega et al ., 2015). …”

Section: Introductionmentioning

confidence: 99%

CALHM1 and its polymorphism P86L differentially control Ca²⁺ homeostasis, mitogen‐activated protein kinase signaling, and cell vulnerability upon exposure to amyloid β

et al. 2015

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SummaryThe mutated form of the Ca2+ channel CALHM1 (Ca2+ homeostasis modulator 1), P86L‐CALHM1, has been correlated with early onset of Alzheimer's disease (AD). P86L‐CALHM1 increases production of amyloid beta (Aβ) upon extracellular Ca2+ removal and its subsequent addback. The aim of this study was to investigate the effect of the overexpression of CALHM1 and P86L‐CALHM, upon Aβ treatment, on the following: (i) the intracellular Ca2+ signal pathway; (ii) cell survival proteins ERK1/2 and Ca2+/cAMP response element binding (CREB); and (iii) cell vulnerability after treatment with Aβ. Using aequorins to measure the effect of nuclear Ca2+ concentrations ([Ca2+]n) and cytosolic Ca2+ concentrations ([Ca2+]c) on Ca2+ entry conditions, we observed that baseline [Ca2+]n was higher in CALHM1 and P86L‐CALHM1 cells than in control cells. Moreover, exposure to Aβ affected [Ca2+]c levels in HeLa cells overexpressing CALHM1 and P86L‐CALHM1 compared with control cells. Treatment with Aβ elicited a significant decrease in the cell survival proteins p‐ERK and p‐CREB, an increase in the activity of caspases 3 and 7, and more frequent cell death by inducing early apoptosis in P86L‐CALHM1‐overexpressing cells than in CALHM1 or control cells. These results suggest that in the presence of Aβ, P86L‐CALHM1 shifts the balance between neurodegeneration and neuronal survival toward the stimulation of pro‐cytotoxic pathways, thus potentially contributing to its deleterious effects in AD.

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Reductive Activation of Aryl Chlorides by Tuning the Radical Cation Properties of N‐Phenylphenothiazines as Organophotoredox Catalysts

Weick,

Hagmeyer,

Giraud

et al. 2023

Chemistry A European J

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Aryl chlorides as substrates for arylations present a particular challenge for photoredox catalytic activation due to their strong C(sp2)‑Cl bond and their strong reduction potential. Electron‐rich N‐phenyl phenothiazines, as organophotoredox catalysts, are capable to cleave aryl chlorides simply by photoinduced electron transfer without the need for an additional electrochemical activation setup or any other advanced photocatalysis technique. Due to the extremely strong reduction potential in the excited state of the N‐phenylphenothiazines the substrate scope is high and includes aryl chlorides both with electron‐withdrawing and electron‐donating substituents. We evidence this reactivity for photocatalytic borylations and phosphonylations. Advanced time‐resolved transient absorption spectroscopy in combination with electrochemistry was the key to elucidate and compare not only the unusual photophysical properties of the N‐phenylphenothiazines, but also of their cation radicals as the central intermediates in the photocatalytic cycle. The revealed photophysics allowed the fine‐tuning of the excited state and radical cation properties by the molecular design of the N‐phenyl phenothiazines which improved the photocatalytic activity.

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Benzothiazepine CGP37157 and its 2′-isopropyl analogue modulate Ca2+ entry through CALHM1

Cited by 22 publications

References 28 publications

Molecular and Pharmacological Modulation of CALHM1 Promote Neuroprotection against Oxygen and Glucose Deprivation in a Model of Hippocampal Slices

Molecular and Pharmacological Modulation of CALHM1 Promote Neuroprotection against Oxygen and Glucose Deprivation in a Model of Hippocampal Slices

CALHM1 and its polymorphism P86L differentially control Ca²⁺ homeostasis, mitogen‐activated protein kinase signaling, and cell vulnerability upon exposure to amyloid β

Reductive Activation of Aryl Chlorides by Tuning the Radical Cation Properties of N‐Phenylphenothiazines as Organophotoredox Catalysts

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Benzothiazepine CGP37157 and its 2′-isopropyl analogue modulate Ca2+ entry through CALHM1

Cited by 22 publications

References 28 publications

Molecular and Pharmacological Modulation of CALHM1 Promote Neuroprotection against Oxygen and Glucose Deprivation in a Model of Hippocampal Slices

Molecular and Pharmacological Modulation of CALHM1 Promote Neuroprotection against Oxygen and Glucose Deprivation in a Model of Hippocampal Slices

CALHM1 and its polymorphism P86L differentially control Ca2+ homeostasis, mitogen‐activated protein kinase signaling, and cell vulnerability upon exposure to amyloid β

Reductive Activation of Aryl Chlorides by Tuning the Radical Cation Properties of N‐Phenylphenothiazines as Organophotoredox Catalysts

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CALHM1 and its polymorphism P86L differentially control Ca²⁺ homeostasis, mitogen‐activated protein kinase signaling, and cell vulnerability upon exposure to amyloid β