New Experimental Trends for Phosphoinositides Research on Ion Transporter/Channel Regulation

Mori, Masayuki; Inoue, Ryuji

doi:10.1254/jphs.14r14cp

Cited by 5 publications

(7 citation statements)

References 135 publications

(107 reference statements)

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“…To test this hypothesis, we coexpressed a voltage-sensing lipid phosphatase (Dr-VSP) with TREK-2 in HEK293T. Membrane depolarization activates Dr-VSP, thereby decreasing the level of PI(4,5)P 2 in the plasma membrane [12,25], which should influence the activities of ion channels [24]. The cells were initially held at −80 mV to prevent activation of Dr-VSP and then subjected to sustained depolarization to 20 mV.…”

Section: Inhibition Of Trek-1 By Both Atp and Pi(45)pmentioning

confidence: 99%

Inhibition of TREK-2 K+ channels by PI(4,5)P2: an intrinsic mode of regulation by intracellular ATP via phosphatidylinositol kinase

Woo

Shin

Kim

et al. 2016

Pflugers Arch - Eur J Physiol

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TWIK-related two-pore domain K(+) channels 1 and 2 (TREKs) are activated under various physicochemical conditions. However, the directions in which they are regulated by PI(4,5)P2 and intracellular ATP are not clearly presented yet. In this study, we investigated the effects of ATP and PI(4,5)P2 on overexpressed TREKs (HEK293T and COS-7) and endogenously expressed TREK-2 (mouse astrocytes and WEHI-231 B cells). In all of these cells, both TREK-1 and TREK-2 currents were spontaneously increased by dialysis with ATP-free pipette solution for whole-cell recording (ITREK-1,w-c and ITREK-2w-c) or by membrane excision for inside-out patch clamping without ATP (ITREK-1,i-o and ITREK-2,i-o). Steady state ITREK-2,i-o was reversibly decreased by 3 mM ATP applied to the cytoplasmic side, and this reduction was prevented by wortmannin, a PI-kinase inhibitor. An exogenous application of PI(4,5)P2 inhibited the spontaneously increased ITREKs,i-o, suggesting that intrinsic PI(4,5)P2 maintained by intracellular ATP and PI kinase may set the basal activity of TREKs in the intact cells. The inhibition of intrinsic TREK-2 by ATP was more prominent in WEHI-231 cells than astrocytes. Interestingly, unspecific screening of negative charges by poly-L-lysine also inhibited ITREK-2,i-o. Application of PI(4,5)P2 after the poly-L-lysine treatment showed dose-dependent dual effects, initial activation and subsequent inhibition of ITREK-2,i-o at low and high concentrations, respectively. In HEK293T cells coexpressing TREK-2 and a voltage-sensitive PI(4,5)P2 phosphatase, sustained depolarization increased ITREK-2,w-c initially (<5 s) but then decreased the current below the control level. In HEK293T cells coexpressing TREK-2 and type 3 muscarinic receptor, application of carbachol induced transient activation and sustained suppression of ITREK-2,w-c and cell-attached ITREK-2. The inhibition of TREK-2 by unspecific electrostatic quenching, extensive dephosphorylation, or sustained hydrolysis of PI(4,5)P2 suggests the existence of dual regulatory modes that depend on PI(4,5)P2 concentration.

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Section: Inhibition Of Trek-1 By Both Atp and Pi(45)pmentioning

confidence: 99%

Inhibition of TREK-2 K+ channels by PI(4,5)P2: an intrinsic mode of regulation by intracellular ATP via phosphatidylinositol kinase

Woo

Shin

Kim

et al. 2016

Pflugers Arch - Eur J Physiol

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“…The phosphoinositide PI(3,5)P 2 is an endo-lysosome-specific lipid and considered to be a non-selective endolysosomal channel modulator (McCartney et al, 2014) similar to the role played by PI(4,5)P 2 at the plasma membrane (Mori and Inoue, 2014). Indeed, PI(3,5)P 2 has been shown to modulate currents across endo-lysosomal membranes that were originally attributed to TRPML1 (Dong et al, 2010; Feng et al, 2014).…”

Section: Use Of Tpcn Mutant Linesmentioning

confidence: 99%

Two-Pore Channels: Lessons from Mutant Mouse Models

Ruas¹,

Galione²,

Parrington³

2015

messenger

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Recent interest in two-pore channels (TPCs) has resulted in a variety of studies dealing with the functional role and mechanism of action of these endo-lysosomal proteins in diverse physiological processes. With the availability of mouse lines harbouring mutant alleles for Tpcnl and/or Tpcn2 genes, several studies have made use of them to validate, consolidate and discover new roles for these channels not only at the cellular level but, importantly, also at the level of the whole organism. The different mutant mouse lines that have been used were derived from distinct genetic manipulation strategies, with the aim of knocking out expression of TPC proteins. However, the expression of different residual TPC sequences predicted to occur in these mutant mouse lines, together with the varied degree to which the effects on Tpcn expression have been studied, makes it important to assess the true knockout status of some of the lines. In this review we summarize these Tpcn mutant mouse lines with regard to their predicted effect on Tpcn expression and the extent to which they have been characterized. Additionally, we discuss how results derived from studies using these Tpcn mutant mouse lines have consolidated previously proposed roles for TPCs, such as mediators of NAADP signalling, endo-lysosomal functions, and pancreatic β cell physiology. We will also review how they have been instrumental in the assignment of new physiological roles for these cation channels in processes such as membrane electrical excitability, neoangiogenesis, viral infection and brown adipose tissue and heart function, revealing, in some cases, a specific contribution of a particular TPC isoform.

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“…Nonetheless, as with the aforementioned TRPV channels, the effect of PI(4,5)P 2 is controversial. It is noteworthy that the controversial reports, which are well-reviewed ( Rohacs, 2013 ), utilized different cell settings and different approaches to manipulating PI(4,5)P 2 levels, which raises questions as to whether the PI(4,5)P 2 manipulations in these studies are comparable ( Mori and Inoue, 2014 ). To overcome that potential limitation, the clear-cut effects of the voltage-sensing phosphatase (VSP) are discussed in the next section.…”

Section: Controversial Pi(45)p 2 Effects In Trp Cmentioning

confidence: 99%

Dynamics of receptor-operated Ca2+ currents through TRPC channels controlled via the PI(4,5)P2-PLC signaling pathway

et al. 2015

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Transient receptor potential canonical (TRPC) channels are Ca2+-permeable, nonselective cation channels that carry receptor-operated Ca2+ currents (ROCs) triggered by receptor-induced, phospholipase C (PLC)-catalyzed hydrolysis of phosphatidylinositol 4,5-bisphosphate [PI(4,5)P2]. Within the vasculature, TRPC channel ROCs contribute to smooth muscle cell depolarization, vasoconstriction, and vascular remodeling. However, TRPC channel ROCs exhibit a variable response to receptor-stimulation, and the regulatory mechanisms governing TRPC channel activity remain obscure. The variability of ROCs may be explained by their complex regulation by PI(4,5)P2 and its metabolites, which differentially affect TRPC channel activity. To resolve the complex regulation of ROCs, the use of voltage-sensing phosphoinositide phosphatases and model simulation have helped to reveal the time-dependent contribution of PI(4,5)P2 and the possible role of PI(4,5)P2 in the regulation of ROCs. These approaches may provide unprecedented insight into the dynamics of PI(4,5)P2 regulation of TRPC channels and the fundamental mechanisms underlying transmembrane ion flow. Within that context, we summarize the regulation of TRPC channels and their coupling to receptor-mediated signaling, as well as the application of voltage-sensing phosphoinositide phosphatases to this research. We also discuss the controversial bidirectional effects of PI(4,5)P2 using a model simulation that could explain the complicated effects of PI(4,5)P2 on different ROCs.

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New Experimental Trends for Phosphoinositides Research on Ion Transporter/Channel Regulation

Cited by 5 publications

References 135 publications

Inhibition of TREK-2 K+ channels by PI(4,5)P2: an intrinsic mode of regulation by intracellular ATP via phosphatidylinositol kinase

Inhibition of TREK-2 K+ channels by PI(4,5)P2: an intrinsic mode of regulation by intracellular ATP via phosphatidylinositol kinase

Two-Pore Channels: Lessons from Mutant Mouse Models

Dynamics of receptor-operated Ca2+ currents through TRPC channels controlled via the PI(4,5)P2-PLC signaling pathway

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