Beta-3 Adrenoceptor Signaling Pathways in Urothelial and Smooth Muscle Cells in the Presence of Succinate [Cellular and Molecular]
Mossa, A., Velasquez Flores, M., Nguyen, H., Cammisotto, P. G., Campeau, L.
The American Society for Pharmacology and Experimental Therapeutics
Published 2018
The American Society for Pharmacology and Experimental Therapeutics
Published 2018
| Publication Date: |
2018-10-03
|
|---|---|
| Publisher: |
The American Society for Pharmacology and Experimental Therapeutics
|
| Print ISSN: |
0022-3565
|
| Electronic ISSN: |
1521-0103
|
| Topics: |
Medicine
|
| Published by: |
| _version_ | 1836399061334228994 |
|---|---|
| autor | Mossa, A., Velasquez Flores, M., Nguyen, H., Cammisotto, P. G., Campeau, L. |
| beschreibung | Succinate, an intermediate metabolite of the Krebs cycle, can alter the metabolomics response to certain drugs and controls an array of molecular responses in the urothelium through activation of its receptor, G-protein coupled receptor 91 (GPR91). Mirabegron, a β 3-adrenergic receptor ( β 3-AR) agonist used to treat overactive bladder syndrome (OAB), increases intracellular cAMP in the detrusor smooth muscle cells (SMC), leading to relaxation. We have previously shown that succinate inhibits forskolin-stimulated cAMP production in urothelium. To determine whether succinate interferes with mirabegron-mediated bladder relaxation, we examined their individual and synergistic effect in urothelial-cell and SMC signaling. We first confirmed β 3-AR involvement in the mirabegron response by quantifying receptor abundance by immunoblotting in cultured urothelial cells and SMC and cellular localization by immunohistochemistry in rat bladder tissue. Mirabegron increased cAMP levels in SMC but not in urothelial cells, an increase that was inhibited by succinate, suggesting that it impairs cAMP-mediated bladder relaxation by mirabegron. Succinate and mirabegron increased inducible nitric oxide synthesis and nitric oxide secretion only in urothelial cells, suggesting that its release can indirectly induces SMC relaxation. Succinate exposure decreased the expression of β 3-AR protein in whole bladder in vivo and in SMC in vitro, indicating that this metabolite may lead to impaired pharmacodynamics of the bladder. Together, our results demonstrate that increased levels of succinate in settings of metabolic stress (e.g., the metabolic syndrome) may lead to impaired mirabegron and β 3-AR interaction, inhibition of cAMP production, and ultimately requiring mirabegron dose adjustment for its treatment of OAB related to these conditions. |
| citation_standardnr | 6340295 |
| datenlieferant | ipn_articles |
| feed_id | 1930 |
| feed_publisher | The American Society for Pharmacology and Experimental Therapeutics |
| feed_publisher_url | http://www.aspet.org/ |
| insertion_date | 2018-10-03 |
| journaleissn | 1521-0103 |
| journalissn | 0022-3565 |
| publikationsjahr_anzeige | 2018 |
| publikationsjahr_facette | 2018 |
| publikationsjahr_intervall | 7984:2015-2019 |
| publikationsjahr_sort | 2018 |
| publisher | The American Society for Pharmacology and Experimental Therapeutics |
| quelle | Journal of Pharmacology and Experimental Therapeutics |
| relation | http://jpet.aspetjournals.org/cgi/content/short/367/2/252?rss=1 |
| search_space | articles |
| shingle_author_1 | Mossa, A., Velasquez Flores, M., Nguyen, H., Cammisotto, P. G., Campeau, L. |
| shingle_author_2 | Mossa, A., Velasquez Flores, M., Nguyen, H., Cammisotto, P. G., Campeau, L. |
| shingle_author_3 | Mossa, A., Velasquez Flores, M., Nguyen, H., Cammisotto, P. G., Campeau, L. |
| shingle_author_4 | Mossa, A., Velasquez Flores, M., Nguyen, H., Cammisotto, P. G., Campeau, L. |
| shingle_catch_all_1 | Beta-3 Adrenoceptor Signaling Pathways in Urothelial and Smooth Muscle Cells in the Presence of Succinate [Cellular and Molecular] Succinate, an intermediate metabolite of the Krebs cycle, can alter the metabolomics response to certain drugs and controls an array of molecular responses in the urothelium through activation of its receptor, G-protein coupled receptor 91 (GPR91). Mirabegron, a β 3-adrenergic receptor ( β 3-AR) agonist used to treat overactive bladder syndrome (OAB), increases intracellular cAMP in the detrusor smooth muscle cells (SMC), leading to relaxation. We have previously shown that succinate inhibits forskolin-stimulated cAMP production in urothelium. To determine whether succinate interferes with mirabegron-mediated bladder relaxation, we examined their individual and synergistic effect in urothelial-cell and SMC signaling. We first confirmed β 3-AR involvement in the mirabegron response by quantifying receptor abundance by immunoblotting in cultured urothelial cells and SMC and cellular localization by immunohistochemistry in rat bladder tissue. Mirabegron increased cAMP levels in SMC but not in urothelial cells, an increase that was inhibited by succinate, suggesting that it impairs cAMP-mediated bladder relaxation by mirabegron. Succinate and mirabegron increased inducible nitric oxide synthesis and nitric oxide secretion only in urothelial cells, suggesting that its release can indirectly induces SMC relaxation. Succinate exposure decreased the expression of β 3-AR protein in whole bladder in vivo and in SMC in vitro, indicating that this metabolite may lead to impaired pharmacodynamics of the bladder. Together, our results demonstrate that increased levels of succinate in settings of metabolic stress (e.g., the metabolic syndrome) may lead to impaired mirabegron and β 3-AR interaction, inhibition of cAMP production, and ultimately requiring mirabegron dose adjustment for its treatment of OAB related to these conditions. Mossa, A., Velasquez Flores, M., Nguyen, H., Cammisotto, P. G., Campeau, L. The American Society for Pharmacology and Experimental Therapeutics 0022-3565 00223565 1521-0103 15210103 |
| shingle_catch_all_2 | Beta-3 Adrenoceptor Signaling Pathways in Urothelial and Smooth Muscle Cells in the Presence of Succinate [Cellular and Molecular] Succinate, an intermediate metabolite of the Krebs cycle, can alter the metabolomics response to certain drugs and controls an array of molecular responses in the urothelium through activation of its receptor, G-protein coupled receptor 91 (GPR91). Mirabegron, a β 3-adrenergic receptor ( β 3-AR) agonist used to treat overactive bladder syndrome (OAB), increases intracellular cAMP in the detrusor smooth muscle cells (SMC), leading to relaxation. We have previously shown that succinate inhibits forskolin-stimulated cAMP production in urothelium. To determine whether succinate interferes with mirabegron-mediated bladder relaxation, we examined their individual and synergistic effect in urothelial-cell and SMC signaling. We first confirmed β 3-AR involvement in the mirabegron response by quantifying receptor abundance by immunoblotting in cultured urothelial cells and SMC and cellular localization by immunohistochemistry in rat bladder tissue. Mirabegron increased cAMP levels in SMC but not in urothelial cells, an increase that was inhibited by succinate, suggesting that it impairs cAMP-mediated bladder relaxation by mirabegron. Succinate and mirabegron increased inducible nitric oxide synthesis and nitric oxide secretion only in urothelial cells, suggesting that its release can indirectly induces SMC relaxation. Succinate exposure decreased the expression of β 3-AR protein in whole bladder in vivo and in SMC in vitro, indicating that this metabolite may lead to impaired pharmacodynamics of the bladder. Together, our results demonstrate that increased levels of succinate in settings of metabolic stress (e.g., the metabolic syndrome) may lead to impaired mirabegron and β 3-AR interaction, inhibition of cAMP production, and ultimately requiring mirabegron dose adjustment for its treatment of OAB related to these conditions. Mossa, A., Velasquez Flores, M., Nguyen, H., Cammisotto, P. G., Campeau, L. The American Society for Pharmacology and Experimental Therapeutics 0022-3565 00223565 1521-0103 15210103 |
| shingle_catch_all_3 | Beta-3 Adrenoceptor Signaling Pathways in Urothelial and Smooth Muscle Cells in the Presence of Succinate [Cellular and Molecular] Succinate, an intermediate metabolite of the Krebs cycle, can alter the metabolomics response to certain drugs and controls an array of molecular responses in the urothelium through activation of its receptor, G-protein coupled receptor 91 (GPR91). Mirabegron, a β 3-adrenergic receptor ( β 3-AR) agonist used to treat overactive bladder syndrome (OAB), increases intracellular cAMP in the detrusor smooth muscle cells (SMC), leading to relaxation. We have previously shown that succinate inhibits forskolin-stimulated cAMP production in urothelium. To determine whether succinate interferes with mirabegron-mediated bladder relaxation, we examined their individual and synergistic effect in urothelial-cell and SMC signaling. We first confirmed β 3-AR involvement in the mirabegron response by quantifying receptor abundance by immunoblotting in cultured urothelial cells and SMC and cellular localization by immunohistochemistry in rat bladder tissue. Mirabegron increased cAMP levels in SMC but not in urothelial cells, an increase that was inhibited by succinate, suggesting that it impairs cAMP-mediated bladder relaxation by mirabegron. Succinate and mirabegron increased inducible nitric oxide synthesis and nitric oxide secretion only in urothelial cells, suggesting that its release can indirectly induces SMC relaxation. Succinate exposure decreased the expression of β 3-AR protein in whole bladder in vivo and in SMC in vitro, indicating that this metabolite may lead to impaired pharmacodynamics of the bladder. Together, our results demonstrate that increased levels of succinate in settings of metabolic stress (e.g., the metabolic syndrome) may lead to impaired mirabegron and β 3-AR interaction, inhibition of cAMP production, and ultimately requiring mirabegron dose adjustment for its treatment of OAB related to these conditions. Mossa, A., Velasquez Flores, M., Nguyen, H., Cammisotto, P. G., Campeau, L. The American Society for Pharmacology and Experimental Therapeutics 0022-3565 00223565 1521-0103 15210103 |
| shingle_catch_all_4 | Beta-3 Adrenoceptor Signaling Pathways in Urothelial and Smooth Muscle Cells in the Presence of Succinate [Cellular and Molecular] Succinate, an intermediate metabolite of the Krebs cycle, can alter the metabolomics response to certain drugs and controls an array of molecular responses in the urothelium through activation of its receptor, G-protein coupled receptor 91 (GPR91). Mirabegron, a β 3-adrenergic receptor ( β 3-AR) agonist used to treat overactive bladder syndrome (OAB), increases intracellular cAMP in the detrusor smooth muscle cells (SMC), leading to relaxation. We have previously shown that succinate inhibits forskolin-stimulated cAMP production in urothelium. To determine whether succinate interferes with mirabegron-mediated bladder relaxation, we examined their individual and synergistic effect in urothelial-cell and SMC signaling. We first confirmed β 3-AR involvement in the mirabegron response by quantifying receptor abundance by immunoblotting in cultured urothelial cells and SMC and cellular localization by immunohistochemistry in rat bladder tissue. Mirabegron increased cAMP levels in SMC but not in urothelial cells, an increase that was inhibited by succinate, suggesting that it impairs cAMP-mediated bladder relaxation by mirabegron. Succinate and mirabegron increased inducible nitric oxide synthesis and nitric oxide secretion only in urothelial cells, suggesting that its release can indirectly induces SMC relaxation. Succinate exposure decreased the expression of β 3-AR protein in whole bladder in vivo and in SMC in vitro, indicating that this metabolite may lead to impaired pharmacodynamics of the bladder. Together, our results demonstrate that increased levels of succinate in settings of metabolic stress (e.g., the metabolic syndrome) may lead to impaired mirabegron and β 3-AR interaction, inhibition of cAMP production, and ultimately requiring mirabegron dose adjustment for its treatment of OAB related to these conditions. Mossa, A., Velasquez Flores, M., Nguyen, H., Cammisotto, P. G., Campeau, L. The American Society for Pharmacology and Experimental Therapeutics 0022-3565 00223565 1521-0103 15210103 |
| shingle_title_1 | Beta-3 Adrenoceptor Signaling Pathways in Urothelial and Smooth Muscle Cells in the Presence of Succinate [Cellular and Molecular] |
| shingle_title_2 | Beta-3 Adrenoceptor Signaling Pathways in Urothelial and Smooth Muscle Cells in the Presence of Succinate [Cellular and Molecular] |
| shingle_title_3 | Beta-3 Adrenoceptor Signaling Pathways in Urothelial and Smooth Muscle Cells in the Presence of Succinate [Cellular and Molecular] |
| shingle_title_4 | Beta-3 Adrenoceptor Signaling Pathways in Urothelial and Smooth Muscle Cells in the Presence of Succinate [Cellular and Molecular] |
| timestamp | 2025-06-30T23:36:59.271Z |
| titel | Beta-3 Adrenoceptor Signaling Pathways in Urothelial and Smooth Muscle Cells in the Presence of Succinate [Cellular and Molecular] |
| titel_suche | Beta-3 Adrenoceptor Signaling Pathways in Urothelial and Smooth Muscle Cells in the Presence of Succinate [Cellular and Molecular] |
| topic | WW-YZ |
| uid | ipn_articles_6340295 |