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Endocrine Abstracts (2007) 14 S3.1

Department of Physiology, Semmelweis University, Budapest, Hungary.

The octapeptide hormone angiotensin II (Ang II) exerts its major biological effects via angiotensin AT1 receptors (AT1Rs). Signaling of AT1Rs is regulated by ß-arrestins, which bind to activated AT1Rs, uncouple them form G proteins, and initiate their internalization via clathrin-coated pits and cause G protein independent MAP kinase activation. It has been shown previously that AT1Rs internalize via ß-arrestin-dependent and independent mechanisms, whereas angiotensin AT2 receptors, which are unable to internalize, do not bind ß-arrestins. To study the role of G protein independent MAP kinase activation in cells, which endogenously express AT1Rs, a mutant receptor (S109Y) was created, which is unable to bind candesartan. On the other hand, the Ang II binding and Ang II-induced functional responses of the S109Y mutant receptor are completely normal. This mutation was combined with a mutation (DRY/AAY), which can bind to ß-arrestin2, but its G protein coupling is completely impaired. The receptors were expressed in C9 cells, which express endogenous AT1Rs. In the presence of candesartan the Ca2+ signal and MAP kinase activation of the endogenous AT1R was completely eliminated. However, the Ca2+ signal generation and MAP-kinase activation of the S109Y mutant receptor was readily detectable. in the presence of candesartan, which inhibits the endogenous AT1Rs, the combined S109Y and DRY/AAY mutant receptor was unable to induce Ca2+ signal generation, whereas it mediated Ang II-induced MAP kinase activation with a slow kinetics. These data suggest that G protein independent MAP kinase activation can occur in C9 cells.

This work was supported by OTKA T46445 and ETT 447/2006.

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