A Novel Inhibitor of Hypertonicity-Induced Cation Channels in HeLa Cells

Numata, Tomohiro; Wehner, Frank; Okada, Yasunobu

doi:10.2170/physiolsci.sc003007

Cited by 7 publications

(3 citation statements)

References 16 publications

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“…By contrast, mefenamic acids such as tolfenamic acid, flufenamic acid, niflumic acid, meclofenamic acid and DCDPC (3′‐5‐dichlorodiphenylamine‐2‐carboxylic acid) have also been described to modulate a variety of ion channels and enzymes (Gögelein et al ., 1990; Kankaanranta and Moilanen, 1995; Vietri et al ., 2000; Guinamard et al ., 2004; Dvorzhak, 2008; Habjan and Vandenberg, 2009). The use of fenamates to interfere with cellular volume regulation (Jin et al ., 2003; Lambert and Oberwinkler, 2005; Ducharme et al ., 2007; Numata et al ., 2007) as well as reports describing flufenamic acid as a blocker of transient receptor potential (TRP) channels attracted our interest to this group of small compounds (Tesfai et al ., 2001; Lee et al ., 2003; Guinamard et al ., 2004; Hill et al ., 2004; Guilbert et al ., 2009). In fact, the use of flufenamic acid is increasing because of the absence of selective and potent drugs or pharmacological tools to interfere with TRP channel activity.…”

Section: Introductionmentioning

confidence: 99%

Fenamates as TRP channel blockers: mefenamic acid selectively blocks TRPM3

Klose

Straub

Riehle

et al. 2011

British J Pharmacology

103

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BACKGROUND AND PURPOSEFenamates are N-phenyl-substituted anthranilic acid derivatives clinically used as non-steroid anti-inflammatory drugs in pain treatment. Reports describing fenamates as tools to interfere with cellular volume regulation attracted our attention based on our interest in the role of the volume-modulated transient receptor potential (TRP) channels TRPM3 and TRPV4. EXPERIMENTAL APPROACHFirstly, we measured the blocking potencies and selectivities of fenamates on TRPM3 and TRPV4 as well as TRPC6 and TRPM2 by Ca 2+ imaging in the heterologous HEK293 cell system. Secondly, we further investigated the effects of mefenamic acid on cytosolic Ca 2+ and on the membrane voltage in single HEK293 cells that exogenously express TRPM3. Thirdly, in insulinsecreting INS-1E cells, which endogenously express TRPM3, we validated the effect of mefenamic acid on cytosolic Ca 2+ and insulin secretion. KEY RESULTSWe identified and characterized mefenamic acid as a selective and potent TRPM3 blocker, whereas other fenamate structures non-selectively blocked TRPM3, TRPV4, TRPC6 and TRPM2. CONCLUSIONS AND IMPLICATIONSThis study reveals that mefenamic acid selectively inhibits TRPM3-mediated calcium entry. This selectivity was further confirmed using insulin-secreting cells. KATP channel-dependent increases in cytosolic Ca 2+ and insulin secretion were not blocked by mefenamic acid, but the selective stimulation of TRPM3-dependent Ca 2+ entry and insulin secretion induced by pregnenolone sulphate were inhibited. However, the physiological regulator of TRPM3 in insulin-secreting cells remains to be elucidated, as well as the conditions under which the inhibition of TRPM3 can impair pancreatic b-cell function. Our results strongly suggest mefenamic acid is the most selective fenamate to interfere with TRPM3 function.

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Section: Introductionmentioning

confidence: 99%

Fenamates as TRP channel blockers: mefenamic acid selectively blocks TRPM3

Klose

Straub

Riehle

et al. 2011

British J Pharmacology

103

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“…TRPM2 currents are blocked by an antipyretic acid-derivative nonsteroidal anti-inflammatory drug (NSAID), flufenamic acid (FFA), at 50–1000 μM with an IC 50 of 70 μM ( Hill et al, 2004a ). FFA also inhibits HICC/TRPM2-∆C activity ( Wehner et al, 2003b ) with an IC 50 of 117 μM ( Numata et al, 2007c ). However, it must be noted that FFA affects not only TRPM2 but also other ion channels including some chloride, sodium, potassium and calcium channels ( Guinamard et al, 2013 ).…”

Section: Phenotypic Properties and Molecular Structures Of Trpm2 And ...mentioning

confidence: 99%

“…FFA analogs, mefenamic acid (MFA) and niflumic acid (NFA), are also effective to inhibit TRPM2 channels with IC 50 values of 76 and ∼120 μM, respectively ( Chen et al, 2012 ). Another fenamate analog, 2-aminoethoxydiphenyl borate (2-APB), suppresses TRPM2 activity with an IC 50 of 1.2 μM ( Togashi et al, 2008 ) and HICC activity with an IC 50 of 525 μM ( Numata et al, 2007c ). 2-APB is not specific for TRPM2, because it also inhibits other TRPM members ( Togashi et al, 2008 ) including TRPM7 ( Li et al, 2006 ) and multiple TRPC channels ( Xu et al, 2005 ) but activates several TRPV channels ( Hu et al, 2004 ).…”

Section: Phenotypic Properties and Molecular Structures Of Trpm2 And ...mentioning

confidence: 99%

Cell death induction and protection by activation of ubiquitously expressed anion/cation channels. Part 3: the roles and properties of TRPM2 and TRPM7

Okada,

Numata,

Sabirov

et al. 2023

Front. Cell Dev. Biol.

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Cell volume regulation (CVR) is a prerequisite for animal cells to survive and fulfill their functions. CVR dysfunction is essentially involved in the induction of cell death. In fact, sustained normotonic cell swelling and shrinkage are associated with necrosis and apoptosis, and thus called the necrotic volume increase (NVI) and the apoptotic volume decrease (AVD), respectively. Since a number of ubiquitously expressed ion channels are involved in the CVR processes, these volume-regulatory ion channels are also implicated in the NVI and AVD events. In Part 1 and Part 2 of this series of review articles, we described the roles of swelling-activated anion channels called VSOR or VRAC and acid-activated anion channels called ASOR or PAC in CVR and cell death processes. Here, Part 3 focuses on therein roles of Ca2+-permeable non-selective TRPM2 and TRPM7 cation channels activated by stress. First, we summarize their phenotypic properties and molecular structure. Second, we describe their roles in CVR. Since cell death induction is tightly coupled to dysfunction of CVR, third, we focus on their participation in the induction of or protection against cell death under oxidative, acidotoxic, excitotoxic, and ischemic conditions. In this regard, we pay attention to the sensitivity of TRPM2 and TRPM7 to a variety of stress as well as to their capability to physicall and functionally interact with other volume-related channels and membrane enzymes. Also, we summarize a large number of reports hitherto published in which TRPM2 and TRPM7 channels are shown to be involved in cell death associated with a variety of diseases or disorders, in some cases as double-edged swords. Lastly, we attempt to describe how TRPM2 and TRPM7 are organized in the ionic mechanisms leading to cell death induction and protection.

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Hypertonicity-induced cation channels rescue cells from staurosporine-elicited apoptosis

et al. 2008

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Cell shrinkage is one of the earliest events during apoptosis. Cell shrinkage also occurs upon hypertonic stress, and previous work has shown that hypertonicityinduced cation channels (HICCs) underlie a highly efficient mechanism of recovery from cell shrinkage, called the regulatory volume increase (RVI), in many cell types. Here, the effects of HICC activation on staurosporine-induced apoptotic volume decrease (AVD) and apoptosis were studied in HeLa cells by means of electronic cell sizing and whole-cell patch-clamp recording. It was found that hypertonic stress reduces staurosporine-induced AVD and cell death (associated with caspase-3/7 activation and DNA fragmentation), and that this effect was actually due to activation of the HICC. On the other hand, staurosporine was found to significantly reduce osmotic HICC activation. It is concluded that AVD and RVI reflect two fundamentally distinct functional modes in terms of the activity and role of the HICC, in a shrunken cell. Our results also demonstrate, for the first time, the ability of the HICC to rescue cells from the process of programmed cell death.

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A Novel Inhibitor of Hypertonicity-Induced Cation Channels in HeLa Cells

Cited by 7 publications

References 16 publications

Fenamates as TRP channel blockers: mefenamic acid selectively blocks TRPM3

Fenamates as TRP channel blockers: mefenamic acid selectively blocks TRPM3

Cell death induction and protection by activation of ubiquitously expressed anion/cation channels. Part 3: the roles and properties of TRPM2 and TRPM7

Hypertonicity-induced cation channels rescue cells from staurosporine-elicited apoptosis

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