Voltage-dependent Changes of TRPV6-mediated Ca2+ Currents

Bödding, Matthias

doi:10.1074/jbc.m410184200

Cited by 12 publications

(9 citation statements)

References 30 publications

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“…3, E and F). Current potentiation by both 2-APB and positive membrane potentials are consistent with and characteristic for TRPV6, but not store-operated channels (15,19,20). Together, these results suggest a PSGR-mediated activation of TRPV6 channels without substantial involvement of store-operated channels.…”

Section: Psgr Activation Triggers Opening Of a Plasma Membranesupporting

confidence: 66%

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G Protein-coupled Receptor Signaling via Src Kinase Induces Endogenous Human Transient Receptor Potential Vanilloid Type 6 (TRPV6) Channel Activation

Spehr

Gelis

Osterloh

et al. 2011

Journal of Biological Chemistry

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Ca2؉ homeostasis plays a critical role in a variety of cellular processes. We showed previously that stimulation of the prostate-specific G protein-coupled receptor (PSGR) enhances cytosolic Ca 2؉ and inhibits proliferation of prostate cells. Here, we analyzed the signaling mechanisms underlying the PSGR-mediated Ca 2؉ increase. Using complementary molecular, biochemical, electrophysiological, and live-cell imaging techniques, we found that endogenous Ca 2؉ -selective transient receptor potential vanilloid type 6 (TRPV6) channels are critically involved in the PSGR-induced Ca 2؉ signal. Biophysical characterization of the current activated by PSGR stimulation revealed characteristic properties of TRPV6. The molecular identity of the involved channel was confirmed using RNA interference targeting TrpV6. TRPV6-mediated Ca 2؉ influx depended on Src kinase activity. Src kinase activation occurred independently of G protein activation, presumably by direct interaction with PSGR. Taken together, we report that endogenous TRPV6 channels are activated downstream of a G protein-coupled receptor and present the first physiological characterization of these channels in situ. Ca2ϩ ions function as ubiquitous second messengers that control a variety of cellular processes such as differentiation, proliferation, and apoptosis (1). Epithelial cells control their cytosolic Ca 2ϩ level via non-voltage-gated plasma membrane cationic channels and/or depletion of intracellular Ca 2ϩ stores followed by Ca 2ϩ entry via store-operated channels. Several plasma membrane channels have been implicated in modulation of cytosolic Ca 2ϩ in prostate epithelial cells (2-6). Notably, the two highly Ca 2ϩ -selective Ca 2ϩ (re)absorption channels TRPV5 3 and TRPV6 were found to be expressed in prostate cells (7-9). TRPV6 has been proposed to play a role in prostate cancer cell proliferation (9, 10). The biophysical characteristics of recombinantly overexpressed TRPV6 channels have been studied intensively (11). However, no information on channel physiology in native cells is available. Overexpression of TRPV6 leads to constitutively open channels, and so far no activation mechanism has been described (12). We previously reported that activation of PSGR by ␤-ionone induces an increase in cytosolic Ca 2ϩ and a decreased proliferation rate of prostate cancer cells (13). Thus, the aim of the present study was to examine the mechanism of Ca 2ϩ entry into prostate epithelial cells upon stimulation of PSGR, a class A GPCR that was initially identified as a prostate-specific tumor biomarker (14). Here, we identified TRPV6 as an important signaling protein downstream of activated PSGR showing that TRPV6 can function as a receptor-operated channel. We further identified the tyrosine kinase Src as a signaling protein coupling PSGR and TRPV6 independently of G proteins. In this context, we present the first electrophysiological analysis of endogenous TRPV6 channels. EXPERIMENTAL PROCEDURESCell Culture and Transfection-LNCaP cells were maintained in RPMI 1640...

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Section: Psgr Activation Triggers Opening Of a Plasma Membranesupporting

confidence: 66%

“…It is also potentiated by 100 M 2-APB at negative, but not at positive membrane potentials. Both effects are key features of TRPV6 channels and are not observed for store-operated currents (15,19,20). The store-operated channels Orai 1-3 are either inhibited (Orai 1 and 2) or even activated (Orai 3) by this 2-APB concentration (17,18).…”

Section: Discussionmentioning

confidence: 95%

G Protein-coupled Receptor Signaling via Src Kinase Induces Endogenous Human Transient Receptor Potential Vanilloid Type 6 (TRPV6) Channel Activation

Spehr

Gelis

Osterloh

et al. 2011

Journal of Biological Chemistry

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“…Blocking calcium channels with nicardipine reduces calcitriolmediated IL-10 production of B cells by about 35%. This modulation of calcium flux by calcitriol may be due to membrane-associated VDR [46], or the calcium-selective poreforming transmembrane protein TRPV6 [28,30], expression of which is induced by exogenous and autocrine calcitriol in human B cells, as we show here. Only one third of the effect of calcitriol on Il-10 expression is due to indirect calcium-dependent mechanisms.…”

Section: Discussionmentioning

confidence: 68%

“…The calcium-selective pore-forming transmembrane protein TRPV6 (CaT1) facilitates calcium-influx into the cell after depolarization [28] and is known to be induced by vitamin D in several cell types [29]. Trpv6 mRNA was induced upon addition of calcitriol in human B cells, which were activated by CD40 plus IL-4, with or without BCR cross-linking (Fig.…”

Section: Vdr Modulates Calcium Influx and Binds Directly The Il-10 Genementioning

confidence: 99%

1,25‐dihydroxyvitamin D₃ promotes IL‐10 production in human B cells

et al. 2008

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“…In the absence of divalent cations, TRPV6 channels become permeable for monovalent ions (Peng et al 1999;Wissenbach et al 2001;Hoenderop et al 2001;Bödding 2005). In physiological solutions, the selectivity filter of the pore is occupied by Ca 2+ and blocks movement of monovalent ions.…”

Section: Modes Of Activation and Inactivationmentioning

confidence: 99%

Trpv6

Wissenbach¹,

Niemeyer²

Transient Receptor Potential (TRP) Channels

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The ion channel TRPV6 is likely to function as an epithelial calcium channel in organs with high calcium transport requirements such as the intestine, kidney, and placenta. Transcriptional regulation of TRPV6 messenger RNA (mRNA) is controlled by 1,25-dihydroxyvitamin D, which is the active hormonal form of vitamin D3, and by additional calcium-dependent and vitamin D3-independent mechanisms. Under physiological conditions, the conductance of the channel itself is highly calcium-selective and underlies complex inactivation mechanisms triggered by intracellular calcium and magnesium ions. There is growing evidence that transcriptional regulation of TRPV6 in certain tissues undergoing malignant transformation, such as prostate cancer, is linked to cancer progression.

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Voltage-dependent Changes of TRPV6-mediated Ca2+ Currents

Abstract: The physiological role and activation mechanism for most proteins of the transient receptor potential (TRP) family are unknown. This is also the case for the highly

Cited by 12 publications

References 30 publications

G Protein-coupled Receptor Signaling via Src Kinase Induces Endogenous Human Transient Receptor Potential Vanilloid Type 6 (TRPV6) Channel Activation

G Protein-coupled Receptor Signaling via Src Kinase Induces Endogenous Human Transient Receptor Potential Vanilloid Type 6 (TRPV6) Channel Activation

1,25‐dihydroxyvitamin D₃ promotes IL‐10 production in human B cells

Trpv6

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Voltage-dependent Changes of TRPV6-mediated Ca2+ Currents

Abstract: The physiological role and activation mechanism for most proteins of the transient receptor potential (TRP) family are unknown. This is also the case for the highly

Cited by 12 publications

References 30 publications

G Protein-coupled Receptor Signaling via Src Kinase Induces Endogenous Human Transient Receptor Potential Vanilloid Type 6 (TRPV6) Channel Activation

G Protein-coupled Receptor Signaling via Src Kinase Induces Endogenous Human Transient Receptor Potential Vanilloid Type 6 (TRPV6) Channel Activation

1,25‐dihydroxyvitamin D3 promotes IL‐10 production in human B cells

Trpv6

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1,25‐dihydroxyvitamin D₃ promotes IL‐10 production in human B cells