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Mutational Uncoupling of 1A-Adrenergic Receptors from G Proteins Also Uncouples Mitogenic and Transcriptional Responses in PC12 Cells (2003)
| Content Provider | CiteSeerX |
|---|---|
| Author | Robeva, Anna Minneman, Kenneth P. Chen, Zhongjian Lee, Deborah |
| Abstract | Activation of human 1A-adrenergic receptors in PC12 cells causes many second messenger, mitogenic, and transcrip-tional responses. We examined the role of G protein activation in these responses by uncoupling the receptor through deletion of the first three amino acids from the third intracellular loop (208–210). Expression levels of retrovirus-transfected wild-type and 208–210 1A-adrenergic receptors in PC12 cells were sim-ilar and showed identical binding affinities for antagonists. However, the potency of the agonist norepinephrine was in-creased 9-fold by the 208–210 mutation. In PC12 cells express-ing the 208–210 construct, calcium and inositol phosphate responses to norepinephrine were essentially abolished. The strong activation of mitogen-activated protein kinase pathways seen upon stimulation of wild-type 1A-adrenergic receptors in PC12 cells was abolished by the 208–210 mutation, as was activation of the tyrosine kinase Pyk2. Norepinephrine also activates several transcriptional reporters through 1A-adren-ergic receptors in PC12 cells, including reporters for activator protein 1, serum response element, cAMP response element, nuclear factor-B, nuclear factor of activated T cells, -inter-feron-activated sequence, and signal transducer and activator of transcription. All these transcriptional responses were abol-ished by the 208–210 mutation. Overexpression of G16 did not rescue any of these responses. These data suggest that known second messenger, mitogenic, and transcriptional ef-fects of 1A-adrenergic receptors in PC12 cells all require G protein activation. Increasing evidence suggests that G protein-coupled recep-tors (GPCRs) interact directly with other signaling proteins, possibly causing G protein-independent effects of receptor activation. These receptors have long been known to interact with proteins involved in control of receptor sensitivity such as -arrestins and G protein-coupled receptor kinases (Bun-emann and Hosey, 1999). However, evidence has now accu-mulated suggesting that various GPCRs interact with Jak |
| File Format | |
| Publisher Date | 2003-01-01 |
| Access Restriction | Open |
| Content Type | Text |
