The <scp>TRPM</scp>4 channel inhibitor 9‐phenanthrol

Guinamard, Romain; Hof, Thomas; Negro, Christopher A. Del

doi:10.1111/bph.12582

Cited by 80 publications

(99 citation statements)

References 79 publications

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“…9-Phenanthrol specifically targets TRPM4 channels and has been used in a variety of biological preparations to reveal the contribution of these channels in physiological processes (18). The results from the current study suggest a critical role for the TRPM4 channels in human DSM excitability and contractility.…”

mentioning

confidence: 59%

“…This agent has been successfully used to study TRPM4 channel activity in various preparations (18), including rodent DSM (39,44,45). However, recent studies indicated that 9-phenanthrol inhibits transmembrane protein 16A (TMEM16A) channels (5) in vascular smooth muscle and activates intermediate-conductance Ca 2ϩ -activated K ϩ (IK) channels (12) in endothelial cells.…”

Section: Discussionmentioning

confidence: 99%

“…The role of TRPM4 channels in human DSM cell excitability was investigated using the amphotericin B-perforated patch-clamp technique and the novel TRPM4 channel inhibitor 9-phenanthrol (18). The average cell capacitance of all human DSM cells used in this study was 21.9 Ϯ 2.0 pF (n ϭ 37, N ϭ 19).…”

Section: Trpm4 Channel Mrna Detection In Human Dsmmentioning

confidence: 99%

“…A particularly interesting and important member of the TRP channel superfamily is the TRPM4 channel (18,32). This channel is highly permeable to monovalent cations, such as Na ϩ and K ϩ , but impermeable to anions and divalent cations, including Ca 2ϩ (17,32).…”

mentioning

confidence: 99%

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Novel regulatory mechanism in human urinary bladder: central role of transient receptor potential melastatin 4 channels in detrusor smooth muscle function

Hristov

Smith

Parajuli

et al. 2016

American Journal of Physiology-Cell Physiology

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Transient receptor potential melastatin 4 (TRPM4) channels are Ca(2+)-activated nonselective cation channels that have been recently identified as regulators of detrusor smooth muscle (DSM) function in rodents. However, their expression and function in human DSM remain unexplored. We provide insights into the functional role of TRPM4 channels in human DSM under physiological conditions. We used a multidisciplinary experimental approach, including RT-PCR, Western blotting, immunohistochemistry and immunocytochemistry, patch-clamp electrophysiology, and functional studies of DSM contractility. DSM samples were obtained from patients without preoperative overactive bladder symptoms. RT-PCR detected mRNA transcripts for TRPM4 channels in human DSM whole tissue and freshly isolated single cells. Western blotting and immunohistochemistry with confocal microscopy revealed TRPM4 protein expression in human DSM. Immunocytochemistry further detected TRPM4 protein expression in DSM single cells. Patch-clamp experiments showed that 9-phenanthrol, a selective TRPM4 channel inhibitor, significantly decreased the transient inward cation currents and voltage step-induced whole cell currents in freshly isolated human DSM cells. In current-clamp mode, 9-phenanthrol hyperpolarized the human DSM cell membrane potential. Furthermore, 9-phenanthrol attenuated the spontaneous phasic, carbachol-induced and nerve-evoked contractions in human DSM isolated strips. Significant species-related differences in TRPM4 channel activity between human, rat, and guinea pig DSM were revealed, suggesting a more prominent physiological role for the TRPM4 channel in the regulation of DSM function in humans than in rodents. In conclusion, TRPM4 channels regulate human DSM excitability and contractility and are critical determinants of human urinary bladder function. Thus, TRPM4 channels could represent promising novel targets for the pharmacological or genetic control of overactive bladder.

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mentioning

confidence: 59%

Section: Discussionmentioning

confidence: 99%

Section: Trpm4 Channel Mrna Detection In Human Dsmmentioning

confidence: 99%

mentioning

confidence: 99%

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Novel regulatory mechanism in human urinary bladder: central role of transient receptor potential melastatin 4 channels in detrusor smooth muscle function

Hristov

Smith

Parajuli

et al. 2016

American Journal of Physiology-Cell Physiology

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“…Recently, 9-phenanthrol was identified as a selective TRPM4 blocker [7], with an IC 50 of 20 µM in transfected HEK293 cells and an IC 50 of 1 µM in endothelial cells [8, 9]. …”

Section: Introductionmentioning

confidence: 99%

Transient Receptor Potential Melastatin 4 (TRPM4) Contributes to High Salt Diet-Mediated Early-Stage Endothelial Injury

Ding

Ban

Liu

et al. 2017

Cell Physiol Biochem

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Background/Aims: The present study investigated whether the transient receptor potential melastatin 4 (TRPM4) channel plays a role in high salt diet (HSD)-induced endothelial injuries. Methods: Western blotting and immunofluorescence were used to examine TRPM4 expression in the mesenteric endothelium of Dahl salt-sensitive (SS) rats fed a HSD. The MTT, TUNEL, and transwell assays were used to evaluate the cell viability, cell apoptosis, and cell migration, respectively, of human umbilical vein endothelial cells (HUVECs). Enzyme-linked immunosorbent assays were used to determine the concentrations of intercellular adhesion molecule 1 (ICAM-1), vascular cell adhesion protein 1 (VCAM-1), and E-selectin. Carboxy-H2DCFDA, a membrane-permeable reactive oxygen species (ROS)-sensitive fluorescent probe, was used to detect intracellular ROS levels. Results: TRPM4 was mainly expressed near the plasma membrane of mesenteric artery endothelial cells, and its expression level increased in SS hypertensive rats fed a HSD. Its protein expression was significantly upregulated upon treatment with exogenous hydrogen peroxide (H₂O₂) and aldosterone in cultured HUVECs. Cell viability decreased upon treatment with both agents in a concentration-dependent manner, which could be partially reversed by 9-phenanthrol, a specific TRPM4 inhibitor. Exogenous H₂O₂ induced apoptosis, enhanced cell migration, and increased the release of adhesion molecules, including ICAM-1, VCAM-1, and E-selectin, all of which were significantly attenuated upon treatment with 9-phenanthrol. Aldosterone and H₂O₂ induced the accumulation of intracellular ROS, which was significantly inhibited by 9-phenanthrol, suggesting that oxidative stress is one of the mechanisms underlying aldosterone-induced endothelial injury. Conclusions: Given the fact that oxidative stress and high levels of circulating aldosterone are present in hypertensive patients, we suggest that the upregulation of TRPM4 in the vascular endothelium may be involved in endothelial injuries caused by these stimuli.

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Brain‐Targeted 9‐Phenanthrol‐Loaded Lipid Nanoparticle Prevents Brain Edema after Cerebral Ischemia‐Reperfusion Injury by Inhibiting the Trpm4 Channel in Mice

Liu,

Peng,

et al. 2024

Adv Funct Materials

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Brain edema robustly increases mortality and hinders functional recovery after acute ischemic stroke. However, there are currently no effective therapies available for treating or preventing it. The unchecked opening of the transient receptor potential M4 (TRPM4) channel results in an excessive influx of Na+ and water, which contributes significantly to the formation of brain edema after ischemic stroke. 9‐phenanthrol (9‐Phe), a potent TRPM4 inhibitor, has limited clinical applicability due to its potential cytotoxicity and poor solubility. A brain‐targeting T7 (HAIYPRH)‐modified lipid nanoparticle (LNP) encapsulated 9‐Phe (9‐Phe@T7‐LNP) is designed and synthesized to improve the physicochemical properties and pharmacokinetic properties of 9‐Phe for treating brain edema in vivo. These results demonstrated that 9‐Phe@T7‐LNP can penetrate the intact blood‐brain barrier (BBB) in normal mice and target the brain parenchyma. Moreover, 9‐Phe@T7‐LNP effectively reduced infarct volume and brain edema, prevented neuronal loss and BBB disruption, improved survival, and facilitated neurological function recovery after transient middle cerebral artery occlusion in mice. Additionally, 9‐Phe@T7‐LNP scavenged oxygen‐free radicals and prevented neuronal apoptosis in cultured neurons subjected to oxygen and glucose deprivation/reperfusion. In summary, these findings showed that 9‐Phe@T7‐LNP holds strong potential as a promising targeted therapy for brain edema after stroke, providing superior pharmacological neuroprotection against brain edema.

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The TRPM4 channel inhibitor 9‐phenanthrol

Cited by 80 publications

References 79 publications

Novel regulatory mechanism in human urinary bladder: central role of transient receptor potential melastatin 4 channels in detrusor smooth muscle function

Novel regulatory mechanism in human urinary bladder: central role of transient receptor potential melastatin 4 channels in detrusor smooth muscle function

Transient Receptor Potential Melastatin 4 (TRPM4) Contributes to High Salt Diet-Mediated Early-Stage Endothelial Injury

Brain‐Targeted 9‐Phenanthrol‐Loaded Lipid Nanoparticle Prevents Brain Edema after Cerebral Ischemia‐Reperfusion Injury by Inhibiting the Trpm4 Channel in Mice

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