Pharmacological Modulation and (Patho)Physiological Roles of TRPM4 Channel—Part 1: Modulation of TRPM4

Kovacs, Z; Dienes, Csaba; Hézsô, Tamás; Almássy, János; Magyar, János; Bányász, Tamás; Nánási, Péter P.; Horváth, Balázs; Szentandrássy, Norbert

doi:10.3390/ph15010081

Cited by 8 publications

(3 citation statements)

References 146 publications

(274 reference statements)

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“…TRPM4 is widely expressed in the body and plays important physiological roles in the cardiovascular, immune, endocrine, and nervous systems (Hasan and Zhang 2018, Wang, Xu et al 2019). Pharmacological modulators of TRPM4 have been explored for a variety of conditions, including cancer, stroke, multiple sclerosis and heart disease (Bianchi, Smith and Abriel 2018, Dienes, Kovacs et al 2021, Kovacs, Dienes et al 2022).…”

Section: Resultsmentioning

confidence: 99%

Conservation of the cooling agent binding pocket within the TRPM subfamily

Huffer,

Denley,

Oskoui

et al. 2024

Preprint

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Transient Receptor Potential (TRP) channels are a large and diverse family of tetrameric cation selective channels that are activated by many different types of stimuli, including noxious heat or cold, organic ligands such as vanilloids or cooling agents, or intracellular Ca2+. Structures available for all subtypes of TRP channels reveal that the transmembrane domains are closely related despite their unique sensitivity to activating stimuli. Here we use computational and electrophysiological approaches to explore the conservation of the cooling agent binding pocket identified within the S1-S4 domain of the Melastatin subfamily member TRPM8, the mammalian sensor of noxious cold, with other TRPM channel subtypes. We find that a subset of TRPM channels, including TRPM2, TRPM4 and TRPM5, contain well-conserved cooling agent binding pockets. We then show how the cooling agent icilin modulates activation of TRPM4 to intracellular Ca2+, enhancing the sensitivity of the channel to Ca2+ and diminishing outward-rectification to promote opening at negative voltages. Mutations known to promote or diminish activation of TRPM8 by icilin similarly alter activation of TRPM4 by the cooling agent, suggesting that icilin binds to the cooling agent binding pocket to promote opening of the channel. These findings demonstrate that TRPM4 and TRPM8 channels share related cooling agent binding pockets that are allosterically coupled to opening of the pore.

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Section: Resultsmentioning

confidence: 99%

Conservation of the cooling agent binding pocket within the TRPM subfamily

Huffer,

Denley,

Oskoui

et al. 2024

Preprint

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“…Redox modification of Cys1093 of TRPM4 channels caused reduced desensitization, possibly through increased CaM binding. H 2 O 2 stimulated TRPM4 channels in human umbilical vein cells and through an as-yet-unknown mechanism increased its expression levels (50).…”

Section: Smooth Muscle To Endothelial Communication and Control Of Va...mentioning

confidence: 99%

Flipping Off and On the Redox Switch in the Microcirculation

Katona

Gladwin

Straub

2023

Annu. Rev. Physiol.

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Resistance arteries and arterioles evolved as specialized blood vessels serving two important functions: ( a) regulating peripheral vascular resistance and blood pressure and ( b) matching oxygen and nutrient delivery to metabolic demands of organs. These functions require control of vessel lumen cross-sectional area (vascular tone) via coordinated vascular cell responses governed by precise spatial-temporal communication between intracellular signaling pathways. Herein, we provide a contemporary overview of the significant roles that redox switches play in calcium signaling for orchestrated endothelial, smooth muscle, and red blood cell control of arterial vascular tone. Three interrelated themes are the focus: ( a) smooth muscle to endothelial communication for vasoconstriction, ( b) endothelial to smooth muscle cell cross talk for vasodilation, and ( c) oxygen and red blood cell interregulation of vascular tone and blood flow. We intend for this thematic framework to highlight gaps in our current knowledge and potentially spark interest for cross-disciplinary studies moving forward.

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“…[7][8][9][10] However, the pharmacological toolbox for TRPM4 was limited previously. [11] In our project, we successfully screened for novel small-molecule inhibitors targeting TRPM4 in the low µM and high nM range. In addition, with these inhibitors, we assessed the pathophysiological functions of TRPM4 using biochemical and molecular biology approaches, and in cellular and whole organ assays.…”

Section: Ion Channel Trpm4mentioning

confidence: 99%

Targeting Ion Channel TRPM4

Preti

Rougier

Papapostolou

et al. 2022

Chimia

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The transient receptor potential melastatin 4 (TRPM4) ion channel is ubiquitously expressed. Dysregulation and/or functional mutations of TRPM4 lead to several diseases. Within our studies, we screened for TRPM4 inhibitors and identified small molecules that block TRPM4 in the low µM range. Furthermore, we investigated the pathophysiology of TRPM4 in cardiac conditions, immune diseases and cancer using these novel inhibitors, molecular biology techniques and functional assays.

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Pharmacological Modulation and (Patho)Physiological Roles of TRPM4 Channel—Part 1: Modulation of TRPM4

Cited by 8 publications

References 146 publications

Conservation of the cooling agent binding pocket within the TRPM subfamily

Conservation of the cooling agent binding pocket within the TRPM subfamily

Flipping Off and On the Redox Switch in the Microcirculation

Targeting Ion Channel TRPM4

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