Current understanding of TRPM7 pharmacology and drug development for stroke

Bae, Christine You Jin; Sun, Hong‐Shuo

doi:10.1038/aps.2012.94

Cited by 17 publications

(10 citation statements)

References 71 publications

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“…TRPM2 (Verma et al, 2012), TRPM4 (Loh et al, 2014), and TRPM7 have been implicated in ischemic brain injury (reviewed in Aarts and Tymianski, 2005;Bae and Sun, 2013). In vivo siRNA-mediated silencing of TRPM4 reduces brain infarct volume by half and facilitates functional recovery in rats with middle cerebral artery occlusion (Loh et al, 2014).…”

Section: Trp Channels As Drug Targetsmentioning

confidence: 99%

Transient Receptor Potential Channels as Drug Targets: From the Science of Basic Research to the Art of Medicine

2014

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Section: Trp Channels As Drug Targetsmentioning

confidence: 99%

Transient Receptor Potential Channels as Drug Targets: From the Science of Basic Research to the Art of Medicine

2014

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“…Carvacrol, acting as a TRPM7 inhibitor, protects brain from neonatal hypoxic-ischemic injury (Chen et al, 2015). Thus, TRPM7 becomes a promising therapeutic target for stroke treatment (Bae and Sun, 2011, 2013). …”

Section: Introductionmentioning

confidence: 99%

Deletion of TRPC6 Attenuates NMDA Receptor-Mediated Ca2+ Entry and Ca2+-Induced Neurotoxicity Following Cerebral Ischemia and Oxygen-Glucose Deprivation

Chen

Hatcher

et al. 2017

Front. Neurosci.

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Transient receptor potential canonical 6 (TRPC6) channels are permeable to Na+ and Ca2+ and are widely expressed in the brain. In this study, the role of TRPC6 was investigated following ischemia/reperfusion (I/R) and oxygen-glucose deprivation (OGD). We found that TRPC6 expression was increased in wild-type (WT) mice cortical neurons following I/R and in primary neurons with OGD, and that deletion of TRPC6 reduced the I/R-induced brain infarct in mice and the OGD- /neurotoxin-induced neuronal death. Using live-cell imaging to examine intracellular Ca2+ levels ([Ca2+]i), we found that OGD induced a significant higher increase in glutamate-evoked Ca2+ influx compared to untreated control and such an increase was reduced by TRPC6 deletion. Enhancement of TRPC6 expression using AdCMV-TRPC6-GFP infection in WT neurons increased [Ca2+]i in response to glutamate application compared to AdCMV-GFP control. Inhibition of N-methyl-d-aspartic acid receptor (NMDAR) with MK801 decreased TRPC6-dependent increase of [Ca2+]i in TRPC6 infected cells, indicating that such a Ca2+ influx was NMDAR dependent. Furthermore, TRPC6-dependent Ca2+ influx was blunted by blockade of Na+ entry in TRPC6 infected cells. Finally, OGD-enhanced Ca2+ influx was reduced, but not completely blocked, in the presence of voltage-dependent Na+ channel blocker tetrodotoxin (TTX) and dl-α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) blocker CNQX. Altogether, we concluded that I/R-induced brain damage was, in part, due to upregulation of TRPC6 in cortical neurons. We postulate that overexpression of TRPC6 following I/R may induce neuronal death partially through TRPC6-dependent Na+ entry which activated NMDAR, thus leading to a damaging Ca2+ overload. These findings may provide a potential target for future intervention in stroke-induced brain damage.

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“…These observations strongly support the notion that ROS-mediated TRPM7 activation releases Zn 2+ from intracellular vesicles after Zn 2+ overload. Like the endoplasmic reticulum, these vesicles are a distributed system for divalent cation uptake and release, but in this case the primary divalent ion is Zn 2+ rather than Ca , an ion channel and cytoplasmic kinase, is ubiquitously expressed and essential in early embryonic development (1-4) but also may mediate oxidative stress-induced anoxic neuronal death in adults (5,6). As an ion channel, TRPM7 conducts Zn 2+ >Mg 2+ ∼ Ca 2+ and monovalent cations (7-10) and contributes to labile cytosolic and nuclear Zn 2+ concentrations (8).…”

mentioning

confidence: 99%

TRPM7 senses oxidative stress to release Zn ²⁺ from unique intracellular vesicles

Abiria

Krapivinsky

Sah

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

101

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TRPM7 (transient receptor potential cation channel subfamily M member 7) regulates gene expression and stress-induced cytotoxicity and is required in early embryogenesis through organ development. Here, we show that the majority of TRPM7 is localized in abundant intracellular vesicles. These vesicles (M7Vs) are distinct from endosomes, lysosomes, and other familiar vesicles or organelles. , an ion channel and cytoplasmic kinase, is ubiquitously expressed and essential in early embryonic development (1-4) but also may mediate oxidative stress-induced anoxic neuronal death in adults (5, 6). As an ion channel, TRPM7 conducts Zn 2+ >Mg 2+ ∼ Ca 2+ and monovalent cations (7-10) and contributes to labile cytosolic and nuclear Zn 2+ concentrations (8). TRPM7's C-terminal kinase can phosphorylate multiple substrates (11-13) and is cleaved to release a proapoptotic, chromatin-modifying enzyme (8,14). Zn 2+ regulates TRPM7's kinase activity (11) and binding to transcription factors (8). It is a potent signal for many cellular processes previously related to TRPM7 function, including gene expression, mitosis, and cell survival, but is also proapoptotic at extreme concentrations (15)(16)(17)(18) Oxidative stress increases inward divalent ion permeation through TRPM7 (5, 9), whereas acute and chronic oxidative stress in culture (24-26) or during ischemia-reperfusion in vivo (27, 28) induces TRPM7 expression. The resulting increase in cytosolic Zn 2+ could result in toxic cytosolic concentrations (9). Conversely, reduction of TRPM7 expression protects animals from postischemia reperfusion (5), a condition typically accompanied by increased reactive oxygen species (ROS) and Zn 2+ release from intracellular stores (29). Physiological redox transitions required for stem cell differentiation and gene expression during embryonic development (30, 31) may also be sensed by TRPM7 and transduced via Zn -dependent signals (32). Because TRPM7 patch-clamp recording is limited to the plasma membrane, the assumption has been that TRPM7's main function is on the plasma membrane. However, we have previously shown that TRPM7 is also on intracellular membranes (33-35). Indeed, ROS activation of divalent ion influx through TRPM7 (5, 9) is reminiscent of ROS activation of TRPM2, which releases Ca 2+ and Zn 2+ from lysosomes (36,37 ] and ROS during development and injury.

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Current understanding of TRPM7 pharmacology and drug development for stroke

Cited by 17 publications

References 71 publications

Transient Receptor Potential Channels as Drug Targets: From the Science of Basic Research to the Art of Medicine

Transient Receptor Potential Channels as Drug Targets: From the Science of Basic Research to the Art of Medicine

Deletion of TRPC6 Attenuates NMDA Receptor-Mediated Ca2+ Entry and Ca2+-Induced Neurotoxicity Following Cerebral Ischemia and Oxygen-Glucose Deprivation

TRPM7 senses oxidative stress to release Zn ²⁺ from unique intracellular vesicles

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Current understanding of TRPM7 pharmacology and drug development for stroke

Cited by 17 publications

References 71 publications

Transient Receptor Potential Channels as Drug Targets: From the Science of Basic Research to the Art of Medicine

Transient Receptor Potential Channels as Drug Targets: From the Science of Basic Research to the Art of Medicine

Deletion of TRPC6 Attenuates NMDA Receptor-Mediated Ca2+ Entry and Ca2+-Induced Neurotoxicity Following Cerebral Ischemia and Oxygen-Glucose Deprivation

TRPM7 senses oxidative stress to release Zn 2+ from unique intracellular vesicles

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TRPM7 senses oxidative stress to release Zn ²⁺ from unique intracellular vesicles