Downregulation of TRPV6 channel activity by cholesterol depletion in Jurkat T cell line

Kever, L. V.; Cherezova, Alena; Зенин, В. В.; Negulyaev, Yuri A.; Komissarchik, Ya. Yu.; Semenova, S. B.

doi:10.1002/cbin.11185

Cited by 7 publications

(7 citation statements)

References 43 publications

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“…The notion that TRPV6 functions as the primary epithelial Ca 2+ channel is well supported by findings made in mammalian cells over-expressing TRPV6 (Fecher-Trost et al, 2017) and by measuring endogenous TRPV6-mediated Ca 2+ influx in cultured Jurkat T cells and rat cauda epidermal principle cells (Gao et al, 2016; Kever et al, 2019). Fura-2 Ca 2+ imaging studies in cultured mammalian cells transfected with TRPV6 indicated that this channel is constitutively open (Vennekens et al, 2000).…”

Section: Discussionmentioning

confidence: 84%

Cell-autonomous regulation of epithelial cell quiescence by calcium channel Trpv6

Malick

et al. 2019

eLife

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Epithelial homeostasis and regeneration require a pool of quiescent cells. How the quiescent cells are established and maintained is poorly understood. Here, we report that Trpv6, a cation channel responsible for epithelial Ca2+ absorption, functions as a key regulator of cellular quiescence. Genetic deletion and pharmacological blockade of Trpv6 promoted zebrafish epithelial cells to exit from quiescence and re-enter the cell cycle. Reintroducing Trpv6, but not its channel dead mutant, restored the quiescent state. Ca2+ imaging showed that Trpv6 is constitutively open in vivo. Mechanistically, Trpv6-mediated Ca2+ influx maintained the quiescent state by suppressing insulin-like growth factor (IGF)-mediated Akt-Tor and Erk signaling. In zebrafish epithelia and human colon carcinoma cells, Trpv6/TRPV6 elevated intracellular Ca2+ levels and activated PP2A, which down-regulated IGF signaling and promoted the quiescent state. Our findings suggest that Trpv6 mediates constitutive Ca2+ influx into epithelial cells to continuously suppress growth factor signaling and maintain the quiescent state.

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Section: Discussionmentioning

confidence: 84%

Cell-autonomous regulation of epithelial cell quiescence by calcium channel Trpv6

Malick

et al. 2019

eLife

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“…Thus, it seems possible that those lipids bound under natural conditions has been shown to be, at least in parts, replaced in the excess of CHS [ 32 ]. Yet, consistent with possible binding sites of cholesterol within the channel, there are also functional data indicating that in Jurkat T cells, TRPV6 activity is sensitive to the depletion of this specific lipid [ 33 , 34 ]. Apart from cholesterol, different functional approaches point to phosphatidylinositol-4,5-bisphosphate (PIP 2 ) as an important regulator of TRPV6 and that specific channel characteristics are dependent on the levels of this lipid [ 35 , 36 , 37 , 38 , 39 , 40 , 41 ].…”

Section: Introductionmentioning

confidence: 85%

TRPV6 Regulation by Cis-22a and Cholesterol

et al. 2022

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The highly calcium-selective transient receptor potential vanilloid-type channel TRPV6 is important for epithelial Ca2+ transport. Proper regulation of the inherently constitutively active TRPV6 channels is intricate in preserving Ca2+ homeostasis, whereby structural and functional data suggest that lipids hold an essential role. Altered expression levels or specific TRPV6 mutations may lead to diseases, hence, TRPV6 represents an interesting target for pharmacological modulation. Recent cryo-EM data identified that the specific TRPV6 blocker cis-22a binds, apart from the pore, to a site within the tetrameric channel that largely matches a lipid binding pocket, LBS-2. Therein, cis-22a may replace a lipid such as cholesterol that is bound in the open state. Based on site-directed mutagenesis and functional recordings, we identified and characterized a series of residues within LBS-2 that are essential for TRPV6 inhibition by cis-22a. Additionally, we investigated the modulatory potential of diverse cholesterol depletion efforts on TRPV6 activity. While LBS-2 mutants exhibited altered maximum currents, slow Ca2+-dependent inactivation (SCDI) as well as less inhibition by cis-22a, TRPV6 activity was resistant to cholesterol depletion. Hence, lipids other than cholesterol may predominate TRPV6 regulation when the channel is expressed in HEK293 cells.

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“…TRP vanilloid 5 and 6 (TRPV5 and TRPV6) channels are the most calcium selective channels in the TRP superfamily, with PCa/PNa >100 (compared with 0.3 for TRPM2). Recently, we have provided the first evidence that TRPV6 channel activity and TRPV6‐mediated Ca 2+ influx are dependent on lipid raft integrity in human leukemia Jurkat T‐cells (Kever et al, 2019). Using patch‐clamping and Ca 2+ imaging, we demonstrated that TRPV6‐mediated currents and Ca 2+ influx into Jurkat cells decreased following membrane cholesterol depleting with MβCD.…”

Section: Trp Channels In Lipid Microdomainsmentioning

confidence: 99%

“…It was found that TRPV6 association with lipid rafts and density of TRPV6 channels in the cell membrane declined significantly after disruption of rafts. Hence, lipid rafts regulated the activity of TRPV6 channels and Ca 2+ influx, thus affecting the location and density of channels in the Jurkat T‐cell plasma membrane (Kever et al, 2019).…”

Section: Trp Channels In Lipid Microdomainsmentioning

confidence: 99%

Impact of lipid rafts on transient receptor potential channel activities

Bobkov

Semenova

2022

Journal Cellular Physiology

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Members of the transient receptor potential (TRP) superfamily are cation channels that are expressed in nearly every mammalian cell type and respond as cellular sensors to various environmental stimuli. Light, pressure, osmolarity, temperature, and other stimuli can induce TRP calcium conductivity and correspondingly trigger many signaling processes in cells. Disruption of TRP channel activity, as a rule, harms cellular function. Despite numerous studies, the mechanisms of TRP channel regulation are not yet sufficiently clear, in part, because TRP channels are regulated by a broad set of ligands having diverse physical and chemical features. It is now known that some TRP members are located in membrane microdomains termed lipid rafts. Moreover, interaction between specific raft‐associated lipids with channels may be a key regulation mechanism. This review examines recent findings related to the roles of lipid rafts in regulation of TRP channel activity. The mechanistic events of channel interactions with the main lipid raft constituent, cholesterol, are being clarified. Better understanding of mechanisms behind such interactions would help establish the key elements of TRP channel regulation and hence allow control of cellular responses to environmental stimuli.

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Downregulation of TRPV6 channel activity by cholesterol depletion in Jurkat T cell line

Cited by 7 publications

References 43 publications

Cell-autonomous regulation of epithelial cell quiescence by calcium channel Trpv6

Cell-autonomous regulation of epithelial cell quiescence by calcium channel Trpv6

TRPV6 Regulation by Cis-22a and Cholesterol

Impact of lipid rafts on transient receptor potential channel activities

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