The Ca2+-Activated Monovalent Cation-Selective Channels TRPM4 and TRPM5

Transient receptor potential melastatin 4 (TRPM4) is widely expressed in various organs and associated with cardiovascular and immune diseases. Lately, the interest in studies on TRPM4 in cancer has increased. Thus far, TRPM4 has been investigated in diffuse large B-cell lymphoma, prostate, colorectal, liver, breast, urinary bladder, cervical, and endometrial cancer. In several types of cancer TRPM4 is overexpressed and contributes to cancer hallmark functions such as increased proliferation and migration and cell cycle shift. Hence, TRPM4 is a potential prognostic cancer marker and a promising anticancer drug target candidate. Currently, the underlying mechanism by which TRPM4 contributes to cancer hallmark functions is under investigation. TRPM4 is a Ca2+-activated monovalent cation channel, and its ion conductivity can decrease intracellular Ca2+ signaling. Furthermore, TRPM4 can interact with different partner proteins. However, the lack of potent and specific TRPM4 inhibitors has delayed the investigations of TRPM4. In this review, we summarize the potential mechanisms of action and discuss new small molecule TRPM4 inhibitors, as well as the TRPM4 antibody, M4P. Additionally, we provide an overview of TRPM4 in human cancer and discuss TRPM4 as a diagnostic marker and anticancer drug target.

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Monomethylammonium Ion as a Magnetic Resonance Probe for Monovalent Cation Activators

Journal of Biological Chemistry ◽

10.1016/s0021-9258(19)43377-2 ◽

1973 ◽

Vol 248 (20) ◽

pp. 7191-7196 ◽

Cited By ~ 1

Author(s):

Thomas Nowak

Keyword(s):

Magnetic Resonance ◽

Monovalent Cation

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Specific Ion Effects on the Behavior of Mixtures of Sodium Iso-Butyl Xanthate and Sodium Diethyl Dithiophosphate during the Flotation of a Cu-Ni-PGM Ore: Effects of CaCl2 and NaCl

Environmental Sciences Proceedings ◽

10.3390/iecms2021-10632 ◽

2021 ◽

Vol 6 (1) ◽

pp. 22

Author(s):

Malibongwe S. Manono ◽

Katlego Matibidi ◽

Kirsten C. Corin ◽

Catherine K. Thubakgale ◽

Iyiola O. Otunniyi ◽

...

Keyword(s):

Froth Flotation ◽

Monovalent Cation ◽

Process Water ◽

Polyvalent Cation ◽

Flotation Reagents ◽

Sulfide Flotation ◽

Froth Stability ◽

Ion Effects ◽

The Relationship ◽

Diethyl Dithiophosphate

Inorganic electrolytes present in the process water used during froth flotation may have both beneficial and detrimental effects. These effects are said to be ion specific, as some ions may result in enhanced froth stability, increased mineral recoveries and decreased concentrate grades, while others may bring the opposite effects. Onsite process water quality variations have intensified the need to understand the relationship between inorganic electrolytes and flotation reagents on flotation performance. The use of mixtures of thiol collectors in sulfide flotation is a common practice across the globe; however, very few investigations have considered these in process waters of varying compositions. This study considers the effect of common cations, Na+ and Ca2+, in process water on the behavior of mixtures of thiol collectors. Single-salt solutions of NaCl and CaCl2 at an ionic strength of 0.0213 mol·dm−3 were used to investigate the behavior of mixtures of two thiol collectors. These were carefully selected to understand how mixtures of thiol collectors behave in the presence of a monovalent cation versus a polyvalent cation. Bench-scale froth flotation tests were conducted using a Cu-Ni-PGM ore from the Merensky Reef. The results have shown that the divalent cation, Ca2+, resulted in higher %Cu and %Ni recoveries at all collector mixtures compared to the monovalent cation, Na+. The concentrate grades were, however, slightly compromised, as slightly more gangue reported to the concentrate in the presence of Ca2+. This behavior is attributed to the effect of polyvalent cations on bubble coalescence and froth stability.

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TRPC1, TRPC3, and TRPC4 in Rat Orofacial Structures

Cells Tissues Organs ◽

10.1159/000477665 ◽

2017 ◽

Vol 204 (5-6) ◽

pp. 293-303 ◽

Cited By ~ 1

Author(s):

Masatoshi Fujita ◽

Tadasu Sato ◽

Takehiro Yajima ◽

Eiji Masaki ◽

Hiroyuki Ichikawa

Keyword(s):

Transient Receptor Potential ◽

Sympathetic Neurons ◽

Receptor Potential ◽

Monovalent Cation ◽

Calcitonin Gene ◽

Cervical Ganglion ◽

Parasympathetic Neurons ◽

Transient Receptor ◽

And Function ◽

And Control

TRPC (transient receptor potential cation channel subfamily C) members are nonselective monovalent cation channels and control Ca2+ inflow. In this study, immunohistochemistry for TRPC1, TRPC3, and TRPC4 was performed on rat oral and craniofacial structures to elucidate their distribution and function in the peripheries. In the trigeminal ganglion (TG), 56.1, 84.1, and 68.3% of sensory neurons were immunoreactive (IR) for TRPC1, TRPC3, and TRPC4, respectively. A double immunofluorescence method revealed that small to medium-sized TG neurons co-expressed TRPCs and calcitonin gene-related peptide. In the superior cervical ganglion, all sympathetic neurons showed TRPC1 and TRPC3 immunoreactivity. Parasympathetic neurons in the submandibular ganglion, tongue, and parotid gland were TRPC1, TRPC3, and TRPC4 IR. Gustatory and olfactory cells were also IR for TRPC1, TRPC3, and/or TRPC4. In the musculature, motor endplates expressed TRPC1 and TRPC4 immunoreactivity. It is likely that TRPCs are associated with sensory, autonomic, and motor functions in oral and craniofacial structures.

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Monovalent cation dependence of tissue plasminogen activator synthesis by HeLa cells.

Journal of Biological Chemistry ◽

10.1016/s0021-9258(18)61462-0 ◽

1987 ◽

Vol 262 (7) ◽

pp. 3017-3021

Author(s):

D.J. Crutchley ◽

P.E. Smariga

Keyword(s):

Plasminogen Activator ◽

Tissue Plasminogen Activator ◽

Hela Cells ◽

Monovalent Cation ◽

Tissue Plasminogen

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Development and characterization of a monoclonal antibody blocking human TRPM4 channel

Scientific Reports ◽

10.1038/s41598-021-89935-5 ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

See Wee Low ◽

Yahui Gao ◽

Shunhui Wei ◽

Bo Chen ◽

Bernd Nilius ◽

...

Keyword(s):

Monoclonal Antibody ◽

Rat Model ◽

Therapeutic Potential ◽

Monovalent Cation ◽

Transgenic Animal ◽

Cell Swelling ◽

Live Cells ◽

Prolonged Incubation ◽

Trpm4 Channel

AbstractTRPM4 is a calcium-activated non-selective monovalent cation channel implicated in diseases such as stroke. Lack of potent and selective inhibitors remains a major challenge for studying TRPM4. Using a polypeptide from rat TRPM4, we have generated a polyclonal antibody M4P which could alleviate reperfusion injury in a rat model of stroke. Here, we aim to develop a monoclonal antibody that could block human TRPM4 channel. Two mouse monoclonal antibodies M4M and M4M1 were developed to target an extracellular epitope of human TRPM4. Immunohistochemistry and western blot were used to characterize the binding of these antibodies to human TRPM4. Potency of inhibition was compared using electrophysiological methods. We further evaluated the therapeutic potential on a rat model of middle cerebral artery occlusion. Both M4M and M4M1 could bind to human TRPM4 channel on the surface of live cells. Prolonged incubation with TRPM4 blocking antibody internalized surface TRPM4. Comparing to M4M1, M4M is more effective in blocking human TRPM4 channel. In human brain microvascular endothelial cells, M4M successfully inhibited TRPM4 current and ameliorated hypoxia-induced cell swelling. Using wild type rats, neither antibody demonstrated therapeutic potential on stroke. Human TRPM4 channel can be blocked by a monoclonal antibody M4M targeting a key antigenic sequence. For future clinical translation, the antibody needs to be humanized and a transgenic animal carrying human TRPM4 sequence is required for in vivo characterizing its therapeutic potential.

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An ensemble view of thrombin allostery

Biological Chemistry ◽

10.1515/hsz-2012-0178 ◽

2012 ◽

Vol 393 (9) ◽

pp. 889-898 ◽

Cited By ~ 43

Author(s):

Bernhard C. Lechtenberg ◽

Stefan M.V. Freund ◽

James A. Huntington

Keyword(s):

Structural Changes ◽

Allosteric Regulation ◽

Monovalent Cation ◽

Coagulation Cascade ◽

General View ◽

Multiple Substrates ◽

Dynamic View ◽

Static View ◽

Two State Model ◽

The Continuum

Abstract Thrombin is the central protease of the coagulation cascade. Its activity is tightly regulated to ensure rapid blood clotting while preventing uncontrolled thrombosis. Thrombin interacts with multiple substrates and cofactors and is critically involved in both pro- and anticoagulant pathways of the coagulation network. Its allosteric regulation, especially by the monovalent cation Na+, has been the focus of research for more than 30 years. It is believed that thrombin can adopt an anticoagulant (‘slow’) conformation and, after Na+ binding, a structurally distinct procoagulant (‘fast’) state. In the past few years, however, the general view of allostery has evolved from one of rigid structural changes towards thermodynamic ensembles of conformational states. With this background, the view of the allosteric regulation of thrombin has also changed. The static view of the two-state model has been dismissed in favor of a more dynamic view of thrombin allostery. Herein, we review recent data that demonstrate that apo-thrombin is zymogen-like and exists as an ensemble of conformations. Furthermore, we describe how ligand binding to thrombin allosterically stabilizes conformations on the continuum from zymogen to protease.

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