| First Author | Li X | Year | 2013 |
| Journal | J Biol Chem | Volume | 288 |
| Issue | 47 | Pages | 33797-812 |
| PubMed ID | 24121510 | Mgi Jnum | J:204978 |
| Mgi Id | MGI:5543837 | Doi | 10.1074/jbc.M113.470559 |
| Citation | Li X, et al. (2013) Role of AKAP79/150 protein in beta1-adrenergic receptor trafficking and signaling in mammalian cells. J Biol Chem 288(47):33797-812 |
| abstractText | Protein kinase A-anchoring proteins (AKAPs) participate in the formation of macromolecular signaling complexes that include protein kinases, ion channels, effector enzymes, and G-protein-coupled receptors. We examined the role of AKAP79/150 (AKAP5) in trafficking and signaling of the beta1-adrenergic receptor (beta1-AR). shRNA-mediated down-regulation of AKAP5 in HEK-293 cells inhibited the recycling of the beta1-AR. Recycling of the beta1-AR in AKAP5 knockdown cells was rescued by shRNA-resistant AKAP5. However, truncated mutants of AKAP5 with deletions in the domains involved in membrane targeting or in binding to calcineurin or PKA failed to restore the recycling of the beta1-AR, indicating that full-length AKAP5 was required. Furthermore, recycling of the beta1-AR in rat neonatal cardiac myocytes was dependent on targeting the AKAP5-PKA complex to the C-terminal tail of the beta1-AR. To analyze the role of AKAP5 more directly, recycling of the beta1-AR was determined in ventricular myocytes from AKAP5(-/-) mice. In AKAP5(-/-) myocytes, the agonist-internalized beta1-AR did not recycle, except when full-length AKAP5 was reintroduced. These data indicate that AKAP5 exerted specific and profound effects on beta1-AR recycling in mammalian cells. Biochemical or real time FRET-based imaging of cyclic AMP revealed that deletion of AKAP5 sensitized the cardiac beta1-AR signaling pathway to isoproterenol. Moreover, isoproterenol-mediated increase in contraction rate, surface area, or expression of beta-myosin heavy chains was significantly greater in AKAP5(-/-) myocytes than in AKAP5(+/+) myocytes. These results indicate a significant role for the AKAP5 scaffold in signaling and trafficking of the beta1-AR in cardiac myocytes and mammalian cells. |
