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  • 1
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    Online Resource
    Functional role of TRPC6 and STIM2 in cytosolic and endoplasmic reticulum Ca2+ content in resting estrogen receptor-positive breast cancer cells
    Portland Press Ltd. ; 2020
    In:  Biochemical Journal Vol. 477, No. 17 ( 2020-09-18), p. 3183-3197
    Details
    In: Biochemical Journal, Portland Press Ltd., Vol. 477, No. 17 ( 2020-09-18), p. 3183-3197
    Abstract: TRPC6 forms non-selective cation channels activated by a variety of stimuli that are involved in a wide number of cellular functions. In estrogen receptor-positive (ER+) breast cancer cells, the store-operated Ca2+ entry has been reported to be dependent on STIM1, STIM2 and Orai3, with TRPC6 playing a key role in the activation of store-operated Ca2+ entry as well as in proliferation, migration and viability of breast cancer cells. We have used a combination of biotinylation, Ca2+ imaging as well as protein knockdown and overexpression of a dominant-negative TRPC6 mutant (TRPC6dn) to show that TRPC6 and STIM2 are required for the maintenance of cytosolic and endoplasmic reticulum Ca2+ content under resting conditions in ER+ breast cancer MCF7 cells. These cells exhibit a greater plasma membrane expression of TRPC6 under resting conditions than non-tumoral breast epithelial cells. Attenuation of STIM2, TRPC6 and Orai3, alone or in combination, results in impairment of resting cytosolic and endoplasmic reticulum Ca2+ homeostasis. Similar results were observed when cells were transfected with expression plasmid for TRPC6dn. TRPC6 co-immunoprecipitates with STIM2 in resting MCF7 cells, a process that is impaired by rises in cytosolic Ca2+ concentration. Impairment of TRPC6 function leads to abnormal Ca2+ homeostasis and endoplasmic reticulum stress, thus, suggesting that TRPC6 might be a potential target for the development of anti-tumoral therapies.
    Type of Medium: Online Resource
    ISSN: 0264-6021 , 1470-8728
    URL: Article
    DOI: 10.1042/BCJ20200560
    RVK:
    WA 15000
    Language: English
    Publisher: Portland Press Ltd.
    Publication Date: 2020
    detail.hit.zdb_id: 1473095-9
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  • 2
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    Evidence for secretion-like coupling involving pp60src in the activation and maintenance of store-mediated Ca2+ entry in mouse pancreatic acinar cells
    Portland Press Ltd. ; 2003
    In:  Biochemical Journal Vol. 370, No. 1 ( 2003-02-15), p. 255-263
    Details
    In: Biochemical Journal, Portland Press Ltd., Vol. 370, No. 1 ( 2003-02-15), p. 255-263
    Abstract: Store-mediated Ca2+ entry (SMCE) is one of the main pathways for Ca2+ influx in non-excitable cells. Recent studies favour a secretion-like coupling mechanism to explain SMCE, where Ca2+ entry is mediated by an interaction of the endoplasmic reticulum (ER) with the plasma membrane (PM) and is modulated by the actin cytoskeleton. To explore this possibility further we have now investigated the role of the actin cytoskeleton in the activation and maintenance of SMCE in pancreatic acinar cells, a more specialized secretory cell type which might be an ideal cellular model to investigate further the properties of the secretion-like coupling model. In these cells, the cytoskeletal disrupters cytochalasin D and latrunculin A inhibited both the activation and maintenance of SMCE. In addition, stabilization of a cortical actin barrier by jasplakinolide prevented the activation, but not the maintenance, of SMCE, suggesting that, as for secretion, the actin cytoskeleton plays a double role in SMCE as a negative modulator of the interaction between the ER and PM, but is also required for this mechanism, since the cytoskeleton disrupters impaired Ca2+ entry. Finally, depletion of the intracellular Ca2+ stores induces cytoskeletal association and activation of pp60src, which is independent on Ca2+ entry. pp60src activation requires the integrity of the actin cytoskeleton and participates in the initial phase of the activation of SMCE in pancreatic acinar cells.
    Type of Medium: Online Resource
    ISSN: 0264-6021 , 1470-8728
    URL: Article
    DOI: 10.1042/bj20021505
    RVK:
    WA 15000
    Language: English
    Publisher: Portland Press Ltd.
    Publication Date: 2003
    detail.hit.zdb_id: 1473095-9
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  • 3
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    Ca2+ accumulation into acidic organelles mediated by Ca2+- and vacuolar H+-ATPases in human platelets
    Portland Press Ltd. ; 2005
    In:  Biochemical Journal Vol. 390, No. 1 ( 2005-08-15), p. 243-252
    Details
    In: Biochemical Journal, Portland Press Ltd., Vol. 390, No. 1 ( 2005-08-15), p. 243-252
    Abstract: Most physiological agonists increase cytosolic free [Ca2+]c (cytosolic free Ca2+ co ncentration) to regulate a variety of cellular processes. How different stimuli evoke distinct spatiotemporal Ca2+ responses remains unclear, and the presence of separate intracellular Ca2+ stores might be of great functional relevance. Ca2+ accumulation into intracellular compartments mainly depends on the activity of Ca2+- and H+-ATPases. Platelets present two separate Ca2+ stores differentiated by the distinct sensitivity to thapsigargin and TBHQ [2,5-di-(t-butyl)-1,4-hydroquinone]. Although one store has long been identified as the dense tubular system, the nature of the TBHQ-sensitive store remains uncertain. Treatment of platelets with GPN (glycylphenylalanine-2-naphthylamide) impaired Ca2+ release by TBHQ and reduced that evoked by thrombin. In contrast, GPN did not modify Ca2+ mobilization stimulated by ADP or AVP ([arginine] vasopressin). Treatment with nigericin, a proton carrier, and bafilomycin A1, an inhibitor of the vacuolar H+-ATPase, to dissipate the proton gradient into acidic organelles induces a transient increase in [Ca2+]c that was abolished by previous treatment with the SERCA (sarcoplasmic/endoplasmic-reticulum Ca2+-ATPase) 3 inhibitor TBHQ. Depleted acidic stores after nigericin or bafilomycin A1 were refilled by SERCA 3. Thrombin, but not ADP or AVP, reduces the rise in [Ca2+] c evoked by nigericin and bafilomycin A1. Our results indicate that the TBHQ-sensitive store in human platelets is an acidic organelle whose Ca2+ accumulation is regulated by both Ca2+- and vacuolar H+-ATPases.
    Type of Medium: Online Resource
    ISSN: 0264-6021 , 1470-8728
    URL: Article
    DOI: 10.1042/BJ20050168
    RVK:
    WA 15000
    Language: English
    Publisher: Portland Press Ltd.
    Publication Date: 2005
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  • 4
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    SARAF modulates TRPC1, but not TRPC6, channel function in a STIM1-independent manner
    Portland Press Ltd. ; 2016
    In:  Biochemical Journal Vol. 473, No. 20 ( 2016-10-15), p. 3581-3595
    Details
    In: Biochemical Journal, Portland Press Ltd., Vol. 473, No. 20 ( 2016-10-15), p. 3581-3595
    Abstract: Canonical transient receptor potential-1 (TRPC1) is an almost ubiquitously expressed channel that plays a relevant role in cell function. As other TRPC members, TRPC1 forms receptor-operated cation channels that exhibit both STIM1-dependent and store-independent behaviour. The STIM1 inhibitor SARAF (for store-operated Ca2+ entry (SOCE)-associated regulatory factor) modulates SOCE by interaction with the STIM1 region responsible for Orai1 activation (SOAR). Furthermore, SARAF modulates Ca2+ entry through the arachidonate-regulated Ca2+ (ARC) channels, consisting of Orai1 and Orai3 heteropentamers and plasma membrane-resident STIM1. While a role for STIM1–Orai1-mediated signals has been demonstrated, the possible role of SARAF in TRPC1 function remains unknown. Here, we provide evidence for the interaction of SARAF with TRPC1, independently of STIM1 both in STIM1-deficient NG115-401L cells and SH-SY5Y cells endogenously expressing STIM1. Silencing of SARAF expression in STIM1-deficient cells demonstrated that SARAF plays a negative regulatory role in TRPC1-mediated Ca2+ entry. The interaction of SARAF with TRPC1 in STIM1-deficient cells, as well as with the TRPC1 pool not associated with STIM1 in STIM1-expressing cells was enhanced by stimulation with the physiological agonist ATP. In contrast with TRPC1, we found that the interaction between SARAF and TRPC6 was constitutive rather than inducible by agonist stimulation. Furthermore, we found that SARAF expression silencing was without effect on Ca2+ entry evoked by agonists in TRPC6 overexpressing cells, as well as in Ca2+ influx evoked by the TRPC6 activator Hyp9. These findings provide evidence for a new regulator of TRPC1 channel function and highlight the relevance of SARAF in intracellular Ca2+ homeostasis.
    Type of Medium: Online Resource
    ISSN: 0264-6021 , 1470-8728
    URL: Article
    DOI: 10.1042/BCJ20160348
    RVK:
    WA 15000
    Language: English
    Publisher: Portland Press Ltd.
    Publication Date: 2016
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  • 5
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    Dynamic interaction of hTRPC6 with the Orai1–STIM1 complex or hTRPC3 mediates its role in capacitative or non-capacitative Ca2+ entry pathways
    Portland Press Ltd. ; 2009
    In:  Biochemical Journal Vol. 420, No. 2 ( 2009-06-01), p. 267-277
    Details
    In: Biochemical Journal, Portland Press Ltd., Vol. 420, No. 2 ( 2009-06-01), p. 267-277
    Abstract: TRPC (canonical transient receptor potential) channel subunits have been shown to assemble into homo- or hetero-meric channel complexes, including different Ca2+-handling proteins, required for the activation of CCE (capacitative Ca2+ entry) or NCCE (non-CCE) pathways. In the present study we found evidence for the dynamic interaction between endogenously expressed hTRPC6 (human TRPC6) with either both Orai1 and STIM1 (stromal interaction molecule 1) or hTRPC3 to participate in CCE or NCCE. Electrotransjection of cells with an anti-hTRPC6 antibody, directed towards the C-terminal region, reduces CCE induced by TPEN [N,N,N′,N′-tetrakis-(2-pyridylmethyl)-ethylenediamine], which reduces the intraluminal free Ca2+ concentration. Cell stimulation with thrombin or extensive Ca2+-store depletion by TG (thapsigargin)+ionomycin enhanced the interaction between hTRPC6 and the CCE proteins Orai1 and STIM1. In contrast, stimulation with the diacylglycerol analogue OAG (1-oleoyl-2-acetyl-sn-glycerol) displaces hTRPC6 from Orai1 and STIM1 and enhances the association between hTRPC6 and hTRPC3. The interaction between hTRPC6 and hTRPC3 was abolished by dimethyl-BAPTA [1,2-bis-(o-aminophenoxy)ethane-N,N,N′,N′-tetra-acetic acid] loading, which indicates that this phenomenon is Ca2+-dependent. These findings support the hypothesis that hTRPC6 participates both in CCE and NCCE through its interaction with the Orai1–STIM1 complex or hTRPC3 respectively.
    Type of Medium: Online Resource
    ISSN: 0264-6021 , 1470-8728
    URL: Article
    DOI: 10.1042/BJ20082179
    RVK:
    WA 15000
    Language: English
    Publisher: Portland Press Ltd.
    Publication Date: 2009
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  • 6
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    STIM1 regulates TRPC6 heteromultimerization and subcellular location
    Portland Press Ltd. ; 2014
    In:  Biochemical Journal Vol. 463, No. 3 ( 2014-11-01), p. 373-381
    Details
    In: Biochemical Journal, Portland Press Ltd., Vol. 463, No. 3 ( 2014-11-01), p. 373-381
    Abstract: STIM1 (stromal interaction molecule 1) regulates store-operated channels in the plasma membrane, but the regulation of TRPC (transient receptor potential canonical) heteromultimerization and location by STIM1 is poorly understood. STIM1 is a single transmembrane protein that communicates the filling state of the endoplasmic reticulum to store-operated channels. STIM1 has been reported to regulate the activity of all of the TRPC family members, except TRPC7. TRPC6 has been predominantly associated to second messenger-activated Ca2+ entry pathways. In the present paper we report that STIM1 regulates the expression of TRPC6 in the plasma membrane and evokes translocation of this channel to the endoplasmic reticulum. Attenuation of TRPC6 expression in the plasma membrane resulted in a reduction in the association of this channel with TRPC1 and TRPC3. We have found that expression of TRPC6 in the endoplasmic reticulum results in an increase in the passive Ca2+ efflux and basal cytosolic Ca2+ concentration, but not in the ability of cells to accumulate Ca2+ into the endoplasmic reticulum. We propose a novel mechanism for the regulation of TRPC6 channel location and function by STIM1, probably as a mechanism to modulate second messenger-operated Ca2+ entry while potentiating store-operated Ca2+ influx.
    Type of Medium: Online Resource
    ISSN: 0264-6021 , 1470-8728
    URL: Article
    DOI: 10.1042/BJ20140523
    RVK:
    WA 15000
    Language: English
    Publisher: Portland Press Ltd.
    Publication Date: 2014
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  • 7
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    Two distinct calcium pools in the endoplasmic reticulum of HEK-293T cells
    Portland Press Ltd. ; 2011
    In:  Biochemical Journal Vol. 435, No. 1 ( 2011-04-01), p. 227-235
    Details
    In: Biochemical Journal, Portland Press Ltd., Vol. 435, No. 1 ( 2011-04-01), p. 227-235
    Abstract: Agonist-sensitive intracellular Ca2+ stores may be heterogeneous and exhibit distinct functional features. We have studied the properties of intracellular Ca2+ stores using targeted aequorins for selective measurements in different subcellular compartments. Both, HEK-293T [HEK (human embryonic kidney)-293 cells expressing the large T-antigen of SV40 (simian virus 40)] and HeLa cells accumulated Ca2+ into the ER (endoplasmic reticulum) to near millimolar concentrations and the IP3-generating agonists, carbachol and ATP, mobilized this Ca2+ pool. We find in HEK-293T, but not in HeLa cells, a distinct agonist-releasable Ca2+ pool insensitive to the SERCA (sarco/endoplasmic reticulum Ca2+ ATPase) inhibitor TBH [2,5-di-(t-butyl)-benzohydroquinone] . TG (thapsigargin) and CPA (cyclopiazonic acid) completely emptied this pool, whereas lysosomal disruption or manoeuvres collapsing endomembrane pH gradients did not. Our results indicate that SERCA3d is important for filling the TBH-resistant store as: (i) SERCA3d is more abundant in HEK-293T than in HeLa cells; (ii) the SERCA 3 ATPase activity of HEK-293T cells is not fully blocked by TBH; and (iii) the expression of SERCA3d in HeLa cells generated a TBH-resistant agonist-mobilizable compartment in the ER. Therefore the distribution of SERCA isoforms may originate the heterogeneity of the ER Ca2+ stores and this may be the basis for store specialization in diverse functions. This adds to recent evidence indicating that SERCA3 isoforms may subserve important physiological and pathophysiological mechanisms.
    Type of Medium: Online Resource
    ISSN: 0264-6021 , 1470-8728
    URL: Article
    DOI: 10.1042/BJ20101427
    RVK:
    WA 15000
    Language: English
    Publisher: Portland Press Ltd.
    Publication Date: 2011
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  • 8
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    Homers regulate calcium entry and aggregation in human platelets: a role for Homers in the association between STIM1 and Orai1
    Portland Press Ltd. ; 2012
    In:  Biochemical Journal Vol. 445, No. 1 ( 2012-07-01), p. 29-38
    Details
    In: Biochemical Journal, Portland Press Ltd., Vol. 445, No. 1 ( 2012-07-01), p. 29-38
    Abstract: Homer is a family of cytoplasmic adaptor proteins that play different roles in cell function, including the regulation of G-protein-coupled receptors. These proteins contain an Ena (Enabled)/VASP (vasodilator-stimulated phosphoprotein) homology 1 domain that binds to the PPXXF sequence motif, which is present in different Ca2+-handling proteins such as IP3 (inositol 1,4,5-trisphosphate) receptors and TRPC (transient receptor potential canonical) channels. In the present study we show evidence for a role of Homer proteins in the STIM1 (stromal interaction molecule 1)–Orai1 association, as well as in the TRPC1–IP3RII (type II IP3 receptor) interaction, which might be of relevance in platelet function. Treatment of human platelets with thapsigargin or thrombin results in a Ca2+-independent association of Homer1 with TRPC1 and IP3RII. In addition, thapsigargin and thrombin enhanced the association of Homer1 with STIM1 and Orai1 in a Ca2+-dependent manner. Interference with Homer function by introduction of the synthetic PPKKFR peptide into cells, which emulates the proline-rich sequences of the PPXXF motif, reduced STIM1–Orai1 and TRPC1– IP3RII associations, as compared with the introduction of the inactive PPKKRR peptide. The PPKKFR peptide attenuates thrombin-evoked Ca2+ entry and the maintenance of thapsigargin-induced store-operated Ca2+ entry. Finally, the PPKKFR peptide attenuated thrombin-induced platelet aggregation. The findings of the present study support an important role for Homer proteins in thrombin-stimulated platelet function, which is likely to be mediated by the support of agonist-induced Ca2+ entry.
    Type of Medium: Online Resource
    ISSN: 0264-6021 , 1470-8728
    URL: Article
    DOI: 10.1042/BJ20120471
    RVK:
    WA 15000
    Language: English
    Publisher: Portland Press Ltd.
    Publication Date: 2012
    detail.hit.zdb_id: 1473095-9
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  • 9
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    Differential involvement of thrombin receptors in Ca2+ release from two different intracellular stores in human platelets
    Portland Press Ltd. ; 2007
    In:  Biochemical Journal Vol. 401, No. 1 ( 2007-01-01), p. 167-174
    Details
    In: Biochemical Journal, Portland Press Ltd., Vol. 401, No. 1 ( 2007-01-01), p. 167-174
    Abstract: Physiological agonists increase cytosolic free Ca2+ concentration to regulate a number of cellular processes. The platelet thrombin receptors, PAR (protease-activated receptor) 1 PAR-4 and GPIb-IX-V (glycoprotein Ib-IX-V) have been described as potential contributors of thrombin-induced platelet aggregation. Platelets present two separate Ca2+ stores, the DTS (dense tubular system) and acidic organelles, differentiated by the distinct sensitivity of their respective SERCAs (sarcoplasmic/endoplasmic-reticulum Ca2+-ATPases) to TG (thapsigargin) and TBHQ [2,5-di-(tert-butyl)-1,4-hydroquinone]. However, the involvement of the thrombin receptors in Ca2+ release from each Ca2+ store remains unknown. Depletion of the DTS using ADP, which releases Ca2+ solely from the DTS, in combination with 10 nM TG, to selectively inhibit SERCA2 located on the DTS reduced Ca2+ release evoked by the PAR-1 agonist, SFLLRN, and the PAR-4 agonist, AYPGKF, by 80 and 50% respectively. Desensitization of PAR-1 and PAR-4 or pre-treatment with the PAR-1 and PAR-4 antagonists SCH 79797 and tcY-NH2 reduced Ca2+ mobilization induced by thrombin, and depletion of the DTS after desensitization or blockade of PAR-1 and PAR-4 had no significant effect on Ca2+ release stimulated by thrombin through the GPIb-IX-V receptor. Converse experiments showed that depletion of the acidic stores using TBHQ reduced Ca2+ release evoked by SFLLRN or AYPGKF, by 20 and 50% respectively, and abolished thrombin-stimulated Ca2+ release through the GPIb-IX-V receptor when PAR-1 and PAR-4 had been desensitized or blocked. Our results indicate that thrombin-induced activation of PAR-1 and PAR-4 evokes Ca2+ release from both Ca2+ stores, while activation of GPIb-IX-V by thrombin releases Ca2+ solely from the acidic compartments in human platelets.
    Type of Medium: Online Resource
    ISSN: 0264-6021 , 1470-8728
    URL: Article
    DOI: 10.1042/BJ20060888
    RVK:
    WA 15000
    Language: English
    Publisher: Portland Press Ltd.
    Publication Date: 2007
    detail.hit.zdb_id: 1473095-9
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