| Autor: |
Julia Nevzorova, Tore Bengtsson, Jon Merlin, Olof S. Dallner, Roger J. Summers, Nodi Dehvari, Dana S. Hutchinson, Masaaki Sato, Bronwyn A Evans, Martina Kocan |
| Rok vydání: |
2012 |
| Předmět: |
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| Zdroj: |
British Journal of Pharmacology. 165:1442-1456 |
| ISSN: |
0007-1188 |
| Popis: |
BACKGROUND AND PURPOSE β-Adrenoceptor stimulation induces glucose uptake in several insulin-sensitive tissues by poorly understood mechanisms. EXPERIMENTAL APPROACH We used a model system in CHO-K1 cells expressing the human β2-adrenoceptor and glucose transporter 4 (GLUT4) to investigate the signalling mechanisms involved. KEY RESULTS In CHO-K1 cells, there was no response to β-adrenoceptor agonists. The introduction of β2-adrenoceptors and GLUT4 into these cells caused increased glucose uptake in response to β-adrenoceptor agonists. GLUT4 translocation occurred in response to insulin and β2-adrenoceptor stimulation, although the key insulin signalling intermediate PKB was not phosphorylated in response to β2-adrenoceptor stimulation. Truncation of the C-terminus of the β2-adrenoceptor at position 349 to remove known phosphorylation sites for GPCR kinases (GRKs) or at position 344 to remove an additional PKA site together with the GRK phosphorylation sites did not significantly affect cAMP accumulation but decreased β2-adrenoceptor-stimulated glucose uptake. Furthermore, inhibition of GRK by transfection of the βARKct construct inhibited β2-adrenoceptor-mediated glucose uptake and GLUT4 translocation, and overexpression of a kinase-dead GRK2 mutant (GRK2 K220R) also inhibited GLUT4 translocation. Introducing β2-adrenoceptors lacking phosphorylation sites for GRK or PKA demonstrated that the GRK sites, but not the PKA sites, were necessary for GLUT4 translocation. CONCLUSIONS AND IMPLICATIONS Glucose uptake in response to activation of β2-adrenoceptors involves translocation of GLUT4 in this model system. The mechanism is dependent on the C-terminus of the β2-adrenoceptor, requires GRK phosphorylation sites, and involves a signalling pathway distinct from that stimulated by insulin. |
| Databáze: |
OpenAIRE |
| Externí odkaz: |
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