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Michal Hershfinkel - One of the best experts on this subject based on the ideXlab platform.
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znr GPR39 controls cell migration by orchestrating recruitment of kcc3 into protrusions re organization of actin and activation of mmp
Cell Calcium, 2021Co-Authors: Moumita Chakraborty, Israel Sekler, Hila Asraf, Michal HershfinkelAbstract:Abstract Actin re-organization and degradation of extracellular matrix by metalloproteases (MMPs) facilitate formation of cellular protrusions that are required for cell proliferation and migration. We find that Zn2+ activation of the Gq-coupled receptor ZnR/GPR39 controls these processes by regulating K+/Cl− co-transporter KCC3, which modulates cell volume. Silencing of KCC3 expression or activity reverses ZnR/GPR39 enhancement of cell proliferation, migration and invasion through Matrigel. Activation of ZnR/GPR39 recruits KCC3 into F-actin rich membrane protrusions, suggesting that it can locally control volume changes. Immunofluorescence analysis indicates that Zn2+ activation of ZnR/GPR39 and KCC3 are required to enhance formation of F-actin stress fibers and cellular protrusions. In addition, ZnR/GPR39 upregulation of KCC3-dependent transport increases the activity of matrix metalloproteases MMP2 and MMP9. Our study establishes a mechanism in which ZnR/GPR39 orchestrates localization and activation of KCC3, formation of F-actin rich cell protrusions and activation of MMPs, and thereby controls cell proliferation and migration.
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ZnR/GPR39 controls cell migration by orchestrating recruitment of KCC3 into protrusions, re-organization of actin and activation of MMP.
Cell calcium, 2021Co-Authors: Moumita Chakraborty, Israel Sekler, Hila Asraf, Michal HershfinkelAbstract:Abstract Actin re-organization and degradation of extracellular matrix by metalloproteases (MMPs) facilitate formation of cellular protrusions that are required for cell proliferation and migration. We find that Zn2+ activation of the Gq-coupled receptor ZnR/GPR39 controls these processes by regulating K+/Cl− co-transporter KCC3, which modulates cell volume. Silencing of KCC3 expression or activity reverses ZnR/GPR39 enhancement of cell proliferation, migration and invasion through Matrigel. Activation of ZnR/GPR39 recruits KCC3 into F-actin rich membrane protrusions, suggesting that it can locally control volume changes. Immunofluorescence analysis indicates that Zn2+ activation of ZnR/GPR39 and KCC3 are required to enhance formation of F-actin stress fibers and cellular protrusions. In addition, ZnR/GPR39 upregulation of KCC3-dependent transport increases the activity of matrix metalloproteases MMP2 and MMP9. Our study establishes a mechanism in which ZnR/GPR39 orchestrates localization and activation of KCC3, formation of F-actin rich cell protrusions and activation of MMPs, and thereby controls cell proliferation and migration.
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znr GPR39 upregulation of k cl cotransporter 3 in tamoxifen resistant breast cancer cells
Cell Calcium, 2019Co-Authors: Maayan Mero, Israel Sekler, Hila Asraf, Kathryn Mary Taylor, Michal HershfinkelAbstract:Expression of the zinc receptor, ZnR/GPR39, is increased in higher grade breast cancer tumors and cells. Zinc, its ligand, is accumulated at larger concentrations in the tumor tissue and can therefore activate ZnR/GPR39-dependent Ca2+ signaling leading to tumor progression. The K+/Cl- co-transporters (KCC), activated by intracellular signaling, enhance breast cancer cell migration and invasion. We asked if ZnR/GPR39 enhances breast cancer cell malignancy by activating KCC. Activation of ZnR/GPR39 by Zn2+ upregulated K+/Cl- co-transport activity, measured using NH4+ as a surrogate to K+ while monitoring intracellular pH. Upregulation of NH4+ transport was monitored in tamoxifen resistant cells with functional ZnR/GPR39-dependent Ca2+ signaling but not in MCF-7 cells lacking this response. The NH4+ transport was Na+-independent, and we therefore focused on KCC family members. Silencing of KCC3, but not KCC4, expression abolished Zn2+-dependent K+/Cl- co-transport, suggesting that KCC3 is mediating upregulated NH4+ transport. The ZnR/GPR39-dependent KCC3 activation accelerated scratch closure rate, which was abolished by inhibiting KCC transport with [(DihydroIndenyl) Oxy] Alkanoic acid (DIOA). Importantly, silencing of either ZnR/GPR39 or KCC3 attenuated Zn2+-dependent scratch closure. Thus, a novel link between KCC3 and Zn2+, via ZnR/GPR39, promotes breast cancer cell migration and proliferation.
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ZnR/GPR39 upregulation of K+/Cl−-cotransporter 3 in tamoxifen resistant breast cancer cells
Cell calcium, 2019Co-Authors: Maayan Mero, Israel Sekler, Hila Asraf, Kathryn Mary Taylor, Michal HershfinkelAbstract:Expression of the zinc receptor, ZnR/GPR39, is increased in higher grade breast cancer tumors and cells. Zinc, its ligand, is accumulated at larger concentrations in the tumor tissue and can therefore activate ZnR/GPR39-dependent Ca2+ signaling leading to tumor progression. The K+/Cl- co-transporters (KCC), activated by intracellular signaling, enhance breast cancer cell migration and invasion. We asked if ZnR/GPR39 enhances breast cancer cell malignancy by activating KCC. Activation of ZnR/GPR39 by Zn2+ upregulated K+/Cl- co-transport activity, measured using NH4+ as a surrogate to K+ while monitoring intracellular pH. Upregulation of NH4+ transport was monitored in tamoxifen resistant cells with functional ZnR/GPR39-dependent Ca2+ signaling but not in MCF-7 cells lacking this response. The NH4+ transport was Na+-independent, and we therefore focused on KCC family members. Silencing of KCC3, but not KCC4, expression abolished Zn2+-dependent K+/Cl- co-transport, suggesting that KCC3 is mediating upregulated NH4+ transport. The ZnR/GPR39-dependent KCC3 activation accelerated scratch closure rate, which was abolished by inhibiting KCC transport with [(DihydroIndenyl) Oxy] Alkanoic acid (DIOA). Importantly, silencing of either ZnR/GPR39 or KCC3 attenuated Zn2+-dependent scratch closure. Thus, a novel link between KCC3 and Zn2+, via ZnR/GPR39, promotes breast cancer cell migration and proliferation.
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Enhanced ZnR/GPR39 Activity in Breast Cancer, an Alternative Trigger of Signaling Leading to Cell Growth
Scientific Reports, 2018Co-Authors: Hila Ventura-bixenshpaner, Israel Sekler, Hila Asraf, Moumita Chakraborty, Moshe Elkabets, Kathryn M. Taylor, Michal HershfinkelAbstract:Acquired resistance to the estrogen receptor (ER) antagonist tamoxifen, is a major obstacle in treatment of breast cancer. Changes in Zn^2+ accumulation and distribution are associated with tamoxifen-resistance and breast cancer progression. The Zn^2+-sensing G-protein coupled receptor, ZnR/GPR39, triggers signaling leading to cell growth, but a role for this receptor in breast cancer in unknown. Using fluorescence imaging, we found Zn^2+-dependent Ca^2+ release, mediated by ZnR/GPR39 activity, in TAMR tamoxifen-resistant cells derived from MCF-7 cells, but not in ER-expressing MCF-7 or T47D cells. Furthermore, ZnR/GPR39 signaling was monitored in ER negative BT20, MDA-MB-453 and JIMT-1 cells. Expression of ZnR/GPR39 was increased in grade 3 human breast cancer biopsies compared to grade 2. Consistently, analysis of two breast cancer patient cohorts, GDS4057 and TCGA, indicated that in ER-negative tumors higher ZnR/GPR39 mRNA levels are associated with more aggressive tumors. Activation of ZnR/GPR39 in TAMR cells triggered MAPK, mTOR and PI3K signaling. Importantly, enhanced cell growth and invasiveness was observed in the ER negative breast cancer cells, TAMR, MDA-MB-453 and BT20 cells but not in the ER expressing MCF-7 cells. Thus, we suggest ZnR/GPR39 as a potential therapeutic target for combination treatment in breast cancer, particularly relevant in ER negative tumors.
Gabriel Nowak - One of the best experts on this subject based on the ideXlab platform.
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Long-lasting antidepressant-like activity of the GPR39 zinc receptor agonist TC-G 1008.
Journal of affective disorders, 2018Co-Authors: Gabriela Starowicz, Gabriel Nowak, Beata Ostachowicz, Ewelina Frąckiewicz, Magdalena Jarosz, Natalia Grzechnik, Katarzyna MłyniecAbstract:Abstract Background The discovery of the zinc-sensing receptor, has provided new possibilities for explaining the neurobiology of zinc. Recent studies indicate that the GPR39 zinc receptor may play an important role in the pathogenesis of depression as well as in the antidepressant mechanism of action. Methods In this study we evaluated the time-course of the antidepressant response of the GPR39 agonist (TC-G 1008), imipramine, ZnCl2 and MK-801 in the forced swim test in mice 30 min, 3 h, 6 h and 24 h after acute drug administration as well as after 14-day treatment. Zinc level was measured in serum of mice. BDNF protein level was evaluated in hippocampus following both acute and chronic TC-G 1008 treatment. Results A single administration of the GPR39 agonist caused an antidepressant-like effect lasting up to 24 h following the injection, which is longer than the effect of imipramine, ZnCl2 and MK-801. Chronic treatment with these compounds caused a decrease in immobility time in the FST. Serum zinc concentrations showed an increased level following chronic ZnCl2 administration, but not following administration of TC-G 1008, imipramine or MK-801. We also observed some tendencies for increased BDNF following acute TC-G 1008 treatment. Limitations TC-G 1008 is new drug designed to study GPR39 therefore additional pharmacodynamic and pharmacokinetic properties in preclinical studies are required. Conclusion This study shows for the first time the long-lasting antidepressant effect of the GPR39 agonist in comparison with imipramine, ZnCl2 and MK-801. Our findings suggest that GPR39 should be considered as a target in efforts to develop new antidepressant drugs.
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Potential antidepressant-like properties of the TC G-1008, a GPR39 (zinc receptor) agonist.
Journal of affective disorders, 2016Co-Authors: Katarzyna Młyniec, Magdalena Gaweł, Gabriela Starowicz, Ewelina Frąckiewicz, Gabriel NowakAbstract:Some forms of depression appear to be more related to the glutamatergic system. G-coupled protein receptor 39 (GPR39) is the metabotropic zinc receptor, which may be involved in the pathophysiology of depression and in the antidepressant response. Its deficiency abolishes the antidepressant response, which means that GPR39 is required to obtain a therapeutic effect in depression. This raises the possibility that agonists of the zinc receptor may have a role in antidepressant treatment. To explore this possibility we investigated animal behaviour in the forced swim test, the tail suspension test (to assess antidepressant-like properties), the light/dark test and the elevated plus maze test (to assess anxiolytic-like properties), following acute administration of a GPR39 agonist (TC G-1008). We found an antidepressant response (as measured by the forced swim test but not by the tail suspension test) in mice following the GPR39 agonist treatment. Additionally, we observed the opposite results in the light/dark box (decreased overall distance; increased time spent in the lit compartment; decreased time spent in the dark compartment; increased freezing time) and elevated plus maze (no significant changes), which may be a consequence of the sedative effect of TC G-1008. We also found hippocampal GPR39 and brain-derived neurotrophic factor (BDNF) up-regulation following administration of the GPR39 agonist, which may be undiscovered so far as a possible novel agent in the treatment of mood disorders.
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Immune malfunction in the GPR39 zinc receptor of knockout mice: Its relationship to depressive disorder
Journal of neuroimmunology, 2015Co-Authors: Katarzyna Młyniec, Birgitte Holst, Bogusława Budziszewska, Ewa Trojan, Joanna Ślusarczyk, Katarzyna Głombik, Agnieszka Basta-kaim, Jakub Skrzeszewski, Agata Siwek, Gabriel NowakAbstract:Depression is a serious psychiatric disorder affecting not only the monaminergic, glutamatergic, and GABAergic neurosystems, but also the immune system. Patients suffering from depression show disturbance in the immune parameters as well as increased susceptibility to infections. Zinc is well known as an anti-inflammatory agent, and its link with depression has been proved, zinc deficiency causing depression- and anxiety-like behavior with immune malfunction. It has been discovered that trace-element zinc acts as a neurotransmitter in the central nervous system via zinc receptor GPR39. In this study we investigated whether GPR39 knockout would cause depressive-like behavior as measured by the forced swim test, and whether these changes would coexist with immune malfunction. In GPR39 knockout mice versus a wild-type control we found: i) depressive-like behavior; ii) significantly reduced thymus weight; (iii) reduced cell viability of splenocytes; iv) reduced proliferative response of splenocytes; and v) increased IL-6 production of splenocytes after ConA stimulation and decreased IL-1b and IL-6 release after LPS stimulation. The results indicate depressive-like behavior in GPR39 KO animals with an immune response similar to that observed in depressive disorder. Here for the first time we show immunological changes under GPR39-deficient conditions.
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up regulation of the GPR39 zn 2 sensing receptor and creb bdnf trkb pathway after chronic but not acute antidepressant treatment in the frontal cortex of zinc deficient mice
Pharmacological Reports, 2015Co-Authors: Gabriel Nowak, Katarzyna MlyniecAbstract:Abstract Background The GPR39-Zn 2+ -sensing receptor seems to be involved in the pathophysiology of depression. GPR39 knockout animals show depressive- and anxiety-like behavior. Chronic treatment with selective antidepressants (ADs) up-regulates GPR39. Objective and methods In the present study we investigated whether acute or chronic treatment with imipramine, escitalopram, reboxetine and bupropion would cause changes in CREB, BDNF, TrkB and GPR39-Zn 2+ receptor proteins (measured by Western Blot) in the frontal cortex of mice fed with a low-zinc diet. Results The administration of acute antidepressants induced diverse effects in the proteins that were examined (namely, GPR39 down-regulation and a reduction in CREB protein after administration of all ADs; a decrease in BDNF after administration of imipramine and escitalopram; an increase in BDNF after administration of reboxetine; no change in BDNF following administration of bupropion; and a decrease in TrkB following the administration of all ADs except bupropion). On the other hand, chronic treatment (which is required for depression relief) with all antidepressants increased the levels of all these proteins. Conclusions The present study for the first time demonstrates the up-regulation of GPR39 (and CREB, BDNF, and TrkB) protein when induced by chronic treatment with antidepressants (with different pharmacological profiles) in a zinc-deficiency model in mice. These data further indicate that the GPR39 receptor may be an important target in the antidepressant response.
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Up-regulation of the GPR39 Zn(2+)-sensing receptor and CREB/BDNF/TrkB pathway after chronic but not acute antidepressant treatment in the frontal cortex of zinc-deficient mice
Pharmacological Reports, 2015Co-Authors: Katarzyna Młyniec, Gabriel NowakAbstract:Background The GPR39-Zn^2+-sensing receptor seems to be involved in the pathophysiology of depression. GPR39 knockout animals show depressive- and anxiety-like behavior. Chronic treatment with selective antidepressants (ADs) up-regulates GPR39. Objective and methods In the present study we investigated whether acute or chronic treatment with imipramine, escitalopram, reboxetine and bupropion would cause changes in CREB, BDNF, TrkB and GPR39-Zn^2+ receptor proteins (measured by Western Blot) in the frontal cortex of mice fed with a low-zinc diet. Results The administration of acute antidepressants induced diverse effects in the proteins that were examined (namely, GPR39 down-regulation and a reduction in CREB protein after administration of all ADs; a decrease in BDNF after administration of imipramine and escitalopram; an increase in BDNF after administration of reboxetine; no change in BDNF following administration of bupropion; and a decrease in TrkB following the administration of all ADs except bupropion). On the other hand, chronic treatment (which is required for depression relief) with all antidepressants increased the levels of all these proteins. Conclusions The present study for the first time demonstrates the up-regulation of GPR39 (and CREB, BDNF, and TrkB) protein when induced by chronic treatment with antidepressants (with different pharmacological profiles) in a zinc-deficiency model in mice. These data further indicate that the GPR39 receptor may be an important target in the antidepressant response.
Israel Sekler - One of the best experts on this subject based on the ideXlab platform.
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znr GPR39 controls cell migration by orchestrating recruitment of kcc3 into protrusions re organization of actin and activation of mmp
Cell Calcium, 2021Co-Authors: Moumita Chakraborty, Israel Sekler, Hila Asraf, Michal HershfinkelAbstract:Abstract Actin re-organization and degradation of extracellular matrix by metalloproteases (MMPs) facilitate formation of cellular protrusions that are required for cell proliferation and migration. We find that Zn2+ activation of the Gq-coupled receptor ZnR/GPR39 controls these processes by regulating K+/Cl− co-transporter KCC3, which modulates cell volume. Silencing of KCC3 expression or activity reverses ZnR/GPR39 enhancement of cell proliferation, migration and invasion through Matrigel. Activation of ZnR/GPR39 recruits KCC3 into F-actin rich membrane protrusions, suggesting that it can locally control volume changes. Immunofluorescence analysis indicates that Zn2+ activation of ZnR/GPR39 and KCC3 are required to enhance formation of F-actin stress fibers and cellular protrusions. In addition, ZnR/GPR39 upregulation of KCC3-dependent transport increases the activity of matrix metalloproteases MMP2 and MMP9. Our study establishes a mechanism in which ZnR/GPR39 orchestrates localization and activation of KCC3, formation of F-actin rich cell protrusions and activation of MMPs, and thereby controls cell proliferation and migration.
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ZnR/GPR39 controls cell migration by orchestrating recruitment of KCC3 into protrusions, re-organization of actin and activation of MMP.
Cell calcium, 2021Co-Authors: Moumita Chakraborty, Israel Sekler, Hila Asraf, Michal HershfinkelAbstract:Abstract Actin re-organization and degradation of extracellular matrix by metalloproteases (MMPs) facilitate formation of cellular protrusions that are required for cell proliferation and migration. We find that Zn2+ activation of the Gq-coupled receptor ZnR/GPR39 controls these processes by regulating K+/Cl− co-transporter KCC3, which modulates cell volume. Silencing of KCC3 expression or activity reverses ZnR/GPR39 enhancement of cell proliferation, migration and invasion through Matrigel. Activation of ZnR/GPR39 recruits KCC3 into F-actin rich membrane protrusions, suggesting that it can locally control volume changes. Immunofluorescence analysis indicates that Zn2+ activation of ZnR/GPR39 and KCC3 are required to enhance formation of F-actin stress fibers and cellular protrusions. In addition, ZnR/GPR39 upregulation of KCC3-dependent transport increases the activity of matrix metalloproteases MMP2 and MMP9. Our study establishes a mechanism in which ZnR/GPR39 orchestrates localization and activation of KCC3, formation of F-actin rich cell protrusions and activation of MMPs, and thereby controls cell proliferation and migration.
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ZnR/GPR39 upregulation of K+/Cl−-cotransporter 3 in tamoxifen resistant breast cancer cells
Cell calcium, 2019Co-Authors: Maayan Mero, Israel Sekler, Hila Asraf, Kathryn Mary Taylor, Michal HershfinkelAbstract:Expression of the zinc receptor, ZnR/GPR39, is increased in higher grade breast cancer tumors and cells. Zinc, its ligand, is accumulated at larger concentrations in the tumor tissue and can therefore activate ZnR/GPR39-dependent Ca2+ signaling leading to tumor progression. The K+/Cl- co-transporters (KCC), activated by intracellular signaling, enhance breast cancer cell migration and invasion. We asked if ZnR/GPR39 enhances breast cancer cell malignancy by activating KCC. Activation of ZnR/GPR39 by Zn2+ upregulated K+/Cl- co-transport activity, measured using NH4+ as a surrogate to K+ while monitoring intracellular pH. Upregulation of NH4+ transport was monitored in tamoxifen resistant cells with functional ZnR/GPR39-dependent Ca2+ signaling but not in MCF-7 cells lacking this response. The NH4+ transport was Na+-independent, and we therefore focused on KCC family members. Silencing of KCC3, but not KCC4, expression abolished Zn2+-dependent K+/Cl- co-transport, suggesting that KCC3 is mediating upregulated NH4+ transport. The ZnR/GPR39-dependent KCC3 activation accelerated scratch closure rate, which was abolished by inhibiting KCC transport with [(DihydroIndenyl) Oxy] Alkanoic acid (DIOA). Importantly, silencing of either ZnR/GPR39 or KCC3 attenuated Zn2+-dependent scratch closure. Thus, a novel link between KCC3 and Zn2+, via ZnR/GPR39, promotes breast cancer cell migration and proliferation.
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znr GPR39 upregulation of k cl cotransporter 3 in tamoxifen resistant breast cancer cells
Cell Calcium, 2019Co-Authors: Maayan Mero, Israel Sekler, Hila Asraf, Kathryn Mary Taylor, Michal HershfinkelAbstract:Expression of the zinc receptor, ZnR/GPR39, is increased in higher grade breast cancer tumors and cells. Zinc, its ligand, is accumulated at larger concentrations in the tumor tissue and can therefore activate ZnR/GPR39-dependent Ca2+ signaling leading to tumor progression. The K+/Cl- co-transporters (KCC), activated by intracellular signaling, enhance breast cancer cell migration and invasion. We asked if ZnR/GPR39 enhances breast cancer cell malignancy by activating KCC. Activation of ZnR/GPR39 by Zn2+ upregulated K+/Cl- co-transport activity, measured using NH4+ as a surrogate to K+ while monitoring intracellular pH. Upregulation of NH4+ transport was monitored in tamoxifen resistant cells with functional ZnR/GPR39-dependent Ca2+ signaling but not in MCF-7 cells lacking this response. The NH4+ transport was Na+-independent, and we therefore focused on KCC family members. Silencing of KCC3, but not KCC4, expression abolished Zn2+-dependent K+/Cl- co-transport, suggesting that KCC3 is mediating upregulated NH4+ transport. The ZnR/GPR39-dependent KCC3 activation accelerated scratch closure rate, which was abolished by inhibiting KCC transport with [(DihydroIndenyl) Oxy] Alkanoic acid (DIOA). Importantly, silencing of either ZnR/GPR39 or KCC3 attenuated Zn2+-dependent scratch closure. Thus, a novel link between KCC3 and Zn2+, via ZnR/GPR39, promotes breast cancer cell migration and proliferation.
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enhanced znr GPR39 activity in breast cancer an alternative trigger of signaling leading to cell growth
Scientific Reports, 2018Co-Authors: Hila Venturabixenshpaner, Israel Sekler, Hila Asraf, Kathryn Mary Taylor, Moumita Chakraborty, Moshe Elkabets, Michal HershfinkelAbstract:Acquired resistance to the estrogen receptor (ER) antagonist tamoxifen, is a major obstacle in treatment of breast cancer. Changes in Zn2+ accumulation and distribution are associated with tamoxifen-resistance and breast cancer progression. The Zn2+-sensing G-protein coupled receptor, ZnR/GPR39, triggers signaling leading to cell growth, but a role for this receptor in breast cancer in unknown. Using fluorescence imaging, we found Zn2+-dependent Ca2+ release, mediated by ZnR/GPR39 activity, in TAMR tamoxifen-resistant cells derived from MCF-7 cells, but not in ER-expressing MCF-7 or T47D cells. Furthermore, ZnR/GPR39 signaling was monitored in ER negative BT20, MDA-MB-453 and JIMT-1 cells. Expression of ZnR/GPR39 was increased in grade 3 human breast cancer biopsies compared to grade 2. Consistently, analysis of two breast cancer patient cohorts, GDS4057 and TCGA, indicated that in ER-negative tumors higher ZnR/GPR39 mRNA levels are associated with more aggressive tumors. Activation of ZnR/GPR39 in TAMR cells triggered MAPK, mTOR and PI3K signaling. Importantly, enhanced cell growth and invasiveness was observed in the ER negative breast cancer cells, TAMR, MDA-MB-453 and BT20 cells but not in the ER expressing MCF-7 cells. Thus, we suggest ZnR/GPR39 as a potential therapeutic target for combination treatment in breast cancer, particularly relevant in ER negative tumors.
Hila Asraf - One of the best experts on this subject based on the ideXlab platform.
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znr GPR39 controls cell migration by orchestrating recruitment of kcc3 into protrusions re organization of actin and activation of mmp
Cell Calcium, 2021Co-Authors: Moumita Chakraborty, Israel Sekler, Hila Asraf, Michal HershfinkelAbstract:Abstract Actin re-organization and degradation of extracellular matrix by metalloproteases (MMPs) facilitate formation of cellular protrusions that are required for cell proliferation and migration. We find that Zn2+ activation of the Gq-coupled receptor ZnR/GPR39 controls these processes by regulating K+/Cl− co-transporter KCC3, which modulates cell volume. Silencing of KCC3 expression or activity reverses ZnR/GPR39 enhancement of cell proliferation, migration and invasion through Matrigel. Activation of ZnR/GPR39 recruits KCC3 into F-actin rich membrane protrusions, suggesting that it can locally control volume changes. Immunofluorescence analysis indicates that Zn2+ activation of ZnR/GPR39 and KCC3 are required to enhance formation of F-actin stress fibers and cellular protrusions. In addition, ZnR/GPR39 upregulation of KCC3-dependent transport increases the activity of matrix metalloproteases MMP2 and MMP9. Our study establishes a mechanism in which ZnR/GPR39 orchestrates localization and activation of KCC3, formation of F-actin rich cell protrusions and activation of MMPs, and thereby controls cell proliferation and migration.
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ZnR/GPR39 controls cell migration by orchestrating recruitment of KCC3 into protrusions, re-organization of actin and activation of MMP.
Cell calcium, 2021Co-Authors: Moumita Chakraborty, Israel Sekler, Hila Asraf, Michal HershfinkelAbstract:Abstract Actin re-organization and degradation of extracellular matrix by metalloproteases (MMPs) facilitate formation of cellular protrusions that are required for cell proliferation and migration. We find that Zn2+ activation of the Gq-coupled receptor ZnR/GPR39 controls these processes by regulating K+/Cl− co-transporter KCC3, which modulates cell volume. Silencing of KCC3 expression or activity reverses ZnR/GPR39 enhancement of cell proliferation, migration and invasion through Matrigel. Activation of ZnR/GPR39 recruits KCC3 into F-actin rich membrane protrusions, suggesting that it can locally control volume changes. Immunofluorescence analysis indicates that Zn2+ activation of ZnR/GPR39 and KCC3 are required to enhance formation of F-actin stress fibers and cellular protrusions. In addition, ZnR/GPR39 upregulation of KCC3-dependent transport increases the activity of matrix metalloproteases MMP2 and MMP9. Our study establishes a mechanism in which ZnR/GPR39 orchestrates localization and activation of KCC3, formation of F-actin rich cell protrusions and activation of MMPs, and thereby controls cell proliferation and migration.
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ZnR/GPR39 upregulation of K+/Cl−-cotransporter 3 in tamoxifen resistant breast cancer cells
Cell calcium, 2019Co-Authors: Maayan Mero, Israel Sekler, Hila Asraf, Kathryn Mary Taylor, Michal HershfinkelAbstract:Expression of the zinc receptor, ZnR/GPR39, is increased in higher grade breast cancer tumors and cells. Zinc, its ligand, is accumulated at larger concentrations in the tumor tissue and can therefore activate ZnR/GPR39-dependent Ca2+ signaling leading to tumor progression. The K+/Cl- co-transporters (KCC), activated by intracellular signaling, enhance breast cancer cell migration and invasion. We asked if ZnR/GPR39 enhances breast cancer cell malignancy by activating KCC. Activation of ZnR/GPR39 by Zn2+ upregulated K+/Cl- co-transport activity, measured using NH4+ as a surrogate to K+ while monitoring intracellular pH. Upregulation of NH4+ transport was monitored in tamoxifen resistant cells with functional ZnR/GPR39-dependent Ca2+ signaling but not in MCF-7 cells lacking this response. The NH4+ transport was Na+-independent, and we therefore focused on KCC family members. Silencing of KCC3, but not KCC4, expression abolished Zn2+-dependent K+/Cl- co-transport, suggesting that KCC3 is mediating upregulated NH4+ transport. The ZnR/GPR39-dependent KCC3 activation accelerated scratch closure rate, which was abolished by inhibiting KCC transport with [(DihydroIndenyl) Oxy] Alkanoic acid (DIOA). Importantly, silencing of either ZnR/GPR39 or KCC3 attenuated Zn2+-dependent scratch closure. Thus, a novel link between KCC3 and Zn2+, via ZnR/GPR39, promotes breast cancer cell migration and proliferation.
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znr GPR39 upregulation of k cl cotransporter 3 in tamoxifen resistant breast cancer cells
Cell Calcium, 2019Co-Authors: Maayan Mero, Israel Sekler, Hila Asraf, Kathryn Mary Taylor, Michal HershfinkelAbstract:Expression of the zinc receptor, ZnR/GPR39, is increased in higher grade breast cancer tumors and cells. Zinc, its ligand, is accumulated at larger concentrations in the tumor tissue and can therefore activate ZnR/GPR39-dependent Ca2+ signaling leading to tumor progression. The K+/Cl- co-transporters (KCC), activated by intracellular signaling, enhance breast cancer cell migration and invasion. We asked if ZnR/GPR39 enhances breast cancer cell malignancy by activating KCC. Activation of ZnR/GPR39 by Zn2+ upregulated K+/Cl- co-transport activity, measured using NH4+ as a surrogate to K+ while monitoring intracellular pH. Upregulation of NH4+ transport was monitored in tamoxifen resistant cells with functional ZnR/GPR39-dependent Ca2+ signaling but not in MCF-7 cells lacking this response. The NH4+ transport was Na+-independent, and we therefore focused on KCC family members. Silencing of KCC3, but not KCC4, expression abolished Zn2+-dependent K+/Cl- co-transport, suggesting that KCC3 is mediating upregulated NH4+ transport. The ZnR/GPR39-dependent KCC3 activation accelerated scratch closure rate, which was abolished by inhibiting KCC transport with [(DihydroIndenyl) Oxy] Alkanoic acid (DIOA). Importantly, silencing of either ZnR/GPR39 or KCC3 attenuated Zn2+-dependent scratch closure. Thus, a novel link between KCC3 and Zn2+, via ZnR/GPR39, promotes breast cancer cell migration and proliferation.
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Enhanced ZnR/GPR39 Activity in Breast Cancer, an Alternative Trigger of Signaling Leading to Cell Growth
Scientific Reports, 2018Co-Authors: Hila Ventura-bixenshpaner, Israel Sekler, Hila Asraf, Moumita Chakraborty, Moshe Elkabets, Kathryn M. Taylor, Michal HershfinkelAbstract:Acquired resistance to the estrogen receptor (ER) antagonist tamoxifen, is a major obstacle in treatment of breast cancer. Changes in Zn^2+ accumulation and distribution are associated with tamoxifen-resistance and breast cancer progression. The Zn^2+-sensing G-protein coupled receptor, ZnR/GPR39, triggers signaling leading to cell growth, but a role for this receptor in breast cancer in unknown. Using fluorescence imaging, we found Zn^2+-dependent Ca^2+ release, mediated by ZnR/GPR39 activity, in TAMR tamoxifen-resistant cells derived from MCF-7 cells, but not in ER-expressing MCF-7 or T47D cells. Furthermore, ZnR/GPR39 signaling was monitored in ER negative BT20, MDA-MB-453 and JIMT-1 cells. Expression of ZnR/GPR39 was increased in grade 3 human breast cancer biopsies compared to grade 2. Consistently, analysis of two breast cancer patient cohorts, GDS4057 and TCGA, indicated that in ER-negative tumors higher ZnR/GPR39 mRNA levels are associated with more aggressive tumors. Activation of ZnR/GPR39 in TAMR cells triggered MAPK, mTOR and PI3K signaling. Importantly, enhanced cell growth and invasiveness was observed in the ER negative breast cancer cells, TAMR, MDA-MB-453 and BT20 cells but not in the ER expressing MCF-7 cells. Thus, we suggest ZnR/GPR39 as a potential therapeutic target for combination treatment in breast cancer, particularly relevant in ER negative tumors.
Katarzyna Młyniec - One of the best experts on this subject based on the ideXlab platform.
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Zinc-mediated neurotransmission in Alzheimer's disease: A potential role of the GPR39 in dementia.
Current neuropharmacology, 2019Co-Authors: Michal Rychlik, Katarzyna MłyniecAbstract:With more people reaching an advanced age in modern society, there is a growing need for strategies to slow down age-related neuropathology and loss of cognitive functions, which are a hallmark of Alzheimer's disease. Neuroprotective drugs and candidate drug compounds target one or more processes involved in the neurodegenerative cascade, such as excitotoxicity, oxidative stress, misfolded protein aggregation and/or ion dyshomeostasis. A growing body of research shows that a G-protein coupled zinc (Zn2+) receptor (GPR39) can modulate the abovementioned processes. Zn2+itself has a diverse activity profile at the synapse, and by binding to numerous receptors, it plays an important role in neurotransmission. However, Zn2+ is also necessary for the formation of toxic oligomeric forms of amyloid beta, which underlie the pathology of Alzheimer's disease. Furthermore, the binding of Zn2+ by amyloid beta causes a disruption of zincergic signaling, and recent studies point to GPR39 and its intracellular targets being affected by amyloid pathology. In this review, we present neurobiological findings related to Zn2+ and GPR39, focusing on its signaling pathways, neural plasticity, interactions with other neurotransmission systems, as well as on the effects of pathophysiological changes observed in Alzheimer's disease on GPR39 function. Direct targeting of the GPR39 might be a promising strategy for the pharmacotherapy of zincergic dyshomeostasis observed in Alzheimer's disease. The information presented in this article will hopefully fuel further research into the role of GPR39 in neurodegeneration and help in identifying novel therapeutic targets for dementia.
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Long-lasting antidepressant-like activity of the GPR39 zinc receptor agonist TC-G 1008.
Journal of affective disorders, 2018Co-Authors: Gabriela Starowicz, Gabriel Nowak, Beata Ostachowicz, Ewelina Frąckiewicz, Magdalena Jarosz, Natalia Grzechnik, Katarzyna MłyniecAbstract:Abstract Background The discovery of the zinc-sensing receptor, has provided new possibilities for explaining the neurobiology of zinc. Recent studies indicate that the GPR39 zinc receptor may play an important role in the pathogenesis of depression as well as in the antidepressant mechanism of action. Methods In this study we evaluated the time-course of the antidepressant response of the GPR39 agonist (TC-G 1008), imipramine, ZnCl2 and MK-801 in the forced swim test in mice 30 min, 3 h, 6 h and 24 h after acute drug administration as well as after 14-day treatment. Zinc level was measured in serum of mice. BDNF protein level was evaluated in hippocampus following both acute and chronic TC-G 1008 treatment. Results A single administration of the GPR39 agonist caused an antidepressant-like effect lasting up to 24 h following the injection, which is longer than the effect of imipramine, ZnCl2 and MK-801. Chronic treatment with these compounds caused a decrease in immobility time in the FST. Serum zinc concentrations showed an increased level following chronic ZnCl2 administration, but not following administration of TC-G 1008, imipramine or MK-801. We also observed some tendencies for increased BDNF following acute TC-G 1008 treatment. Limitations TC-G 1008 is new drug designed to study GPR39 therefore additional pharmacodynamic and pharmacokinetic properties in preclinical studies are required. Conclusion This study shows for the first time the long-lasting antidepressant effect of the GPR39 agonist in comparison with imipramine, ZnCl2 and MK-801. Our findings suggest that GPR39 should be considered as a target in efforts to develop new antidepressant drugs.
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Potential antidepressant-like properties of the TC G-1008, a GPR39 (zinc receptor) agonist.
Journal of affective disorders, 2016Co-Authors: Katarzyna Młyniec, Magdalena Gaweł, Gabriela Starowicz, Ewelina Frąckiewicz, Gabriel NowakAbstract:Some forms of depression appear to be more related to the glutamatergic system. G-coupled protein receptor 39 (GPR39) is the metabotropic zinc receptor, which may be involved in the pathophysiology of depression and in the antidepressant response. Its deficiency abolishes the antidepressant response, which means that GPR39 is required to obtain a therapeutic effect in depression. This raises the possibility that agonists of the zinc receptor may have a role in antidepressant treatment. To explore this possibility we investigated animal behaviour in the forced swim test, the tail suspension test (to assess antidepressant-like properties), the light/dark test and the elevated plus maze test (to assess anxiolytic-like properties), following acute administration of a GPR39 agonist (TC G-1008). We found an antidepressant response (as measured by the forced swim test but not by the tail suspension test) in mice following the GPR39 agonist treatment. Additionally, we observed the opposite results in the light/dark box (decreased overall distance; increased time spent in the lit compartment; decreased time spent in the dark compartment; increased freezing time) and elevated plus maze (no significant changes), which may be a consequence of the sedative effect of TC G-1008. We also found hippocampal GPR39 and brain-derived neurotrophic factor (BDNF) up-regulation following administration of the GPR39 agonist, which may be undiscovered so far as a possible novel agent in the treatment of mood disorders.
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Immune malfunction in the GPR39 zinc receptor of knockout mice: Its relationship to depressive disorder
Journal of neuroimmunology, 2015Co-Authors: Katarzyna Młyniec, Birgitte Holst, Bogusława Budziszewska, Ewa Trojan, Joanna Ślusarczyk, Katarzyna Głombik, Agnieszka Basta-kaim, Jakub Skrzeszewski, Agata Siwek, Gabriel NowakAbstract:Depression is a serious psychiatric disorder affecting not only the monaminergic, glutamatergic, and GABAergic neurosystems, but also the immune system. Patients suffering from depression show disturbance in the immune parameters as well as increased susceptibility to infections. Zinc is well known as an anti-inflammatory agent, and its link with depression has been proved, zinc deficiency causing depression- and anxiety-like behavior with immune malfunction. It has been discovered that trace-element zinc acts as a neurotransmitter in the central nervous system via zinc receptor GPR39. In this study we investigated whether GPR39 knockout would cause depressive-like behavior as measured by the forced swim test, and whether these changes would coexist with immune malfunction. In GPR39 knockout mice versus a wild-type control we found: i) depressive-like behavior; ii) significantly reduced thymus weight; (iii) reduced cell viability of splenocytes; iv) reduced proliferative response of splenocytes; and v) increased IL-6 production of splenocytes after ConA stimulation and decreased IL-1b and IL-6 release after LPS stimulation. The results indicate depressive-like behavior in GPR39 KO animals with an immune response similar to that observed in depressive disorder. Here for the first time we show immunological changes under GPR39-deficient conditions.
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Up-regulation of the GPR39 Zn(2+)-sensing receptor and CREB/BDNF/TrkB pathway after chronic but not acute antidepressant treatment in the frontal cortex of zinc-deficient mice
Pharmacological Reports, 2015Co-Authors: Katarzyna Młyniec, Gabriel NowakAbstract:Background The GPR39-Zn^2+-sensing receptor seems to be involved in the pathophysiology of depression. GPR39 knockout animals show depressive- and anxiety-like behavior. Chronic treatment with selective antidepressants (ADs) up-regulates GPR39. Objective and methods In the present study we investigated whether acute or chronic treatment with imipramine, escitalopram, reboxetine and bupropion would cause changes in CREB, BDNF, TrkB and GPR39-Zn^2+ receptor proteins (measured by Western Blot) in the frontal cortex of mice fed with a low-zinc diet. Results The administration of acute antidepressants induced diverse effects in the proteins that were examined (namely, GPR39 down-regulation and a reduction in CREB protein after administration of all ADs; a decrease in BDNF after administration of imipramine and escitalopram; an increase in BDNF after administration of reboxetine; no change in BDNF following administration of bupropion; and a decrease in TrkB following the administration of all ADs except bupropion). On the other hand, chronic treatment (which is required for depression relief) with all antidepressants increased the levels of all these proteins. Conclusions The present study for the first time demonstrates the up-regulation of GPR39 (and CREB, BDNF, and TrkB) protein when induced by chronic treatment with antidepressants (with different pharmacological profiles) in a zinc-deficiency model in mice. These data further indicate that the GPR39 receptor may be an important target in the antidepressant response.
