Mechanisms Responsible for the Trophic Effect of Beta-Adrenoceptors on the Ito Current Density in Type 1 Diabetic Rat Cardiomyocytes
Background/Aims: In diabetic ventricular myocytes, transient outward potassium current (Ito) amplitude is severely reduced because of the impaired catecholamine release that characterizes diabetic autonomic neuropathy. Sympathetic nervous system exhibits a trophic effect on Ito since incubation of m...
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Cell Physiol Biochem Press GmbH & Co KG
2013-01-01
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| Series: | Cellular Physiology and Biochemistry |
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| Online Access: | http://www.karger.com/Article/FullText/343346 |
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| author | Raúl Setién Aintzane Alday Cristina Diaz-Asensio Janire Urrutia Mónica Gallego Oscar Casis |
| author_facet | Raúl Setién Aintzane Alday Cristina Diaz-Asensio Janire Urrutia Mónica Gallego Oscar Casis |
| author_sort | Raúl Setién |
| collection | DOAJ |
| description | Background/Aims: In diabetic ventricular myocytes, transient outward potassium current (Ito) amplitude is severely reduced because of the impaired catecholamine release that characterizes diabetic autonomic neuropathy. Sympathetic nervous system exhibits a trophic effect on Ito since incubation of myocytes with noradrenaline restores current amplitude via beta-adrenoceptor (βAR) stimulation. Here, we investigate the intracellular signalling pathway though which incubation of diabetic cardiomyocytes with the βAR agonist isoproterenol recovers Ito amplitude to normal values. Methods: Experiments were performed in ventricular myocytes isolated from streptozotocin-diabetic rats. Ito current was recorded by using the patch-clamp technique. Kv4 channel expression was determined by immunofluorescence. Protein-protein interaction was determined by coimmunoprecipitation. Results: Stimulation of βAR activates first a Gαs protein, adenylyl cyclase and Protein Kinase A. PKA-phosphorylated receptor then switches to the Gαi protein. This leads to the activation of the βAR-Kinase-1 and further receptor phosphorylation and arrestin dependent internalization. The internalized receptor-arrestin complex recruits and activates cSrc and the MAPK cascade, where Ras, c-Raf1 and finally ERK1/2 mediate the increase in Kv4.2 and Kv4.3 protein abundance in the plasma membrane. Conclusion: β2AR stimulation activates a Gαs and Gαi protein dependent pathway where the ERK1/2 modulates the Ito current amplitude and the density of the Kv4.2 and Kv4.2 channels in the plasma membrane upon sympathetic stimulation in diabetic heart. |
| first_indexed | 2024-04-13T05:16:21Z |
| format | Article |
| id | doaj.art-3b4543e0980c43aba586af51a3a9a09b |
| institution | Directory Open Access Journal |
| issn | 1015-8987 1421-9778 |
| language | English |
| last_indexed | 2024-04-13T05:16:21Z |
| publishDate | 2013-01-01 |
| publisher | Cell Physiol Biochem Press GmbH & Co KG |
| record_format | Article |
| series | Cellular Physiology and Biochemistry |
| spelling | doaj.art-3b4543e0980c43aba586af51a3a9a09b2022-12-22T03:00:52ZengCell Physiol Biochem Press GmbH & Co KGCellular Physiology and Biochemistry1015-89871421-97782013-01-01311253610.1159/000343346343346Mechanisms Responsible for the Trophic Effect of Beta-Adrenoceptors on the Ito Current Density in Type 1 Diabetic Rat CardiomyocytesRaúl SetiénAintzane AldayCristina Diaz-AsensioJanire UrrutiaMónica GallegoOscar CasisBackground/Aims: In diabetic ventricular myocytes, transient outward potassium current (Ito) amplitude is severely reduced because of the impaired catecholamine release that characterizes diabetic autonomic neuropathy. Sympathetic nervous system exhibits a trophic effect on Ito since incubation of myocytes with noradrenaline restores current amplitude via beta-adrenoceptor (βAR) stimulation. Here, we investigate the intracellular signalling pathway though which incubation of diabetic cardiomyocytes with the βAR agonist isoproterenol recovers Ito amplitude to normal values. Methods: Experiments were performed in ventricular myocytes isolated from streptozotocin-diabetic rats. Ito current was recorded by using the patch-clamp technique. Kv4 channel expression was determined by immunofluorescence. Protein-protein interaction was determined by coimmunoprecipitation. Results: Stimulation of βAR activates first a Gαs protein, adenylyl cyclase and Protein Kinase A. PKA-phosphorylated receptor then switches to the Gαi protein. This leads to the activation of the βAR-Kinase-1 and further receptor phosphorylation and arrestin dependent internalization. The internalized receptor-arrestin complex recruits and activates cSrc and the MAPK cascade, where Ras, c-Raf1 and finally ERK1/2 mediate the increase in Kv4.2 and Kv4.3 protein abundance in the plasma membrane. Conclusion: β2AR stimulation activates a Gαs and Gαi protein dependent pathway where the ERK1/2 modulates the Ito current amplitude and the density of the Kv4.2 and Kv4.2 channels in the plasma membrane upon sympathetic stimulation in diabetic heart.http://www.karger.com/Article/FullText/343346RepolarizationAdrenergicArrhythmiaArrestinG protein |
| spellingShingle | Raúl Setién Aintzane Alday Cristina Diaz-Asensio Janire Urrutia Mónica Gallego Oscar Casis Mechanisms Responsible for the Trophic Effect of Beta-Adrenoceptors on the Ito Current Density in Type 1 Diabetic Rat Cardiomyocytes Cellular Physiology and Biochemistry Repolarization Adrenergic Arrhythmia Arrestin G protein |
| title | Mechanisms Responsible for the Trophic Effect of Beta-Adrenoceptors on the Ito Current Density in Type 1 Diabetic Rat Cardiomyocytes |
| title_full | Mechanisms Responsible for the Trophic Effect of Beta-Adrenoceptors on the Ito Current Density in Type 1 Diabetic Rat Cardiomyocytes |
| title_fullStr | Mechanisms Responsible for the Trophic Effect of Beta-Adrenoceptors on the Ito Current Density in Type 1 Diabetic Rat Cardiomyocytes |
| title_full_unstemmed | Mechanisms Responsible for the Trophic Effect of Beta-Adrenoceptors on the Ito Current Density in Type 1 Diabetic Rat Cardiomyocytes |
| title_short | Mechanisms Responsible for the Trophic Effect of Beta-Adrenoceptors on the Ito Current Density in Type 1 Diabetic Rat Cardiomyocytes |
| title_sort | mechanisms responsible for the trophic effect of beta adrenoceptors on the ito current density in type 1 diabetic rat cardiomyocytes |
| topic | Repolarization Adrenergic Arrhythmia Arrestin G protein |
| url | http://www.karger.com/Article/FullText/343346 |
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