RT Journal Article SR Electronic T1 Activation of Signal Transducers and Activators of Transcription by α1A-Adrenergic Receptor Stimulation in PC12 Cells JF Molecular Pharmacology JO Mol Pharmacol FD American Society for Pharmacology and Experimental Therapeutics SP 961 OP 967 VO 57 IS 5 A1 Hongying Zhong A1 T. J. Murphy A1 Kenneth P. Minneman YR 2000 UL http://molpharm.aspetjournals.org/content/57/5/961.abstract AB In PC12 cells stably expressing α1A-adrenergic receptors (ARs), norepinephrine (NE) activates several mitogen-activated protein kinase pathways and causes differentiation (Williams et al., 1998). Using retroviral luciferase reporters, we found that NE also activated both signal transducers and activators of transcription (Stat) and γ-interferon-activated sequence-mediated transcriptional responses, with maximal effects similar to those caused by interleukin-6 (IL-6). UTP and epidermal growth factor had no effect, whereas nerve growth factor caused a small Stat activation. Responses to NE were blocked by prazosin and depended on receptor density. Responses to NE were not blocked by inhibitors of mitogen-activated protein kinase kinase (PD98059), protein kinase C (GFX203290), Src (PP2), Jak2 (AG490), or the calcium chelator 1,2-bis(2-aminophenoxy)ethane-N,N,N′,N′-tetraacetic acid. The p38 mitogen-activated protein kinase inhibitors SB202190 and SB203580 blocked Stat activation by NE, the epidermal growth factor receptor inhibitor AG1478 caused a small inhibition, but the phosphoinositide 3 kinase inhibitor LY294002 potentiated both responses. Gel shifts confirmed formation of nuclear factors binding to both Stat and γ-interferon-activated sequence consensus sequences in response to NE and IL-6. Immunoprecipitation experiments showed that IL-6 increased tyrosine phosphorylation of Stat1 and Stat3 in PC12 cells, whereas NE caused a sustained increase in tyrosine phosphorylation of Stat1. These results suggest that α1A-AR stimulation causes Stat-mediated transcriptional responses in PC12 cells that are not downstream of known second messenger or tyrosine kinase pathways. The American Society for Pharmacology and Experimental Therapeutics