Sandra C Tobias

University of California, San Francisco, San Francisco, California, United States

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Publications (8)33.66 Total impact

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    ABSTRACT: Estrogens and selective estrogen receptor (ER) modulators such as tamoxifen are known to increase uterine cell proliferation. Mounting evidence suggests that estrogen signaling is mediated not only by ERalpha and ERbeta nuclear receptors, but also by GPR30 (GPER), a seven transmembrane (7TM) receptor. Here, we report that primary human endometriotic H-38 cells express high levels of GPR30 with no detectable ERalpha or ERbeta. Using a novel tamoxifen analogue, STX, which activates GPR30 but not ERs, significant stimulation of the phosphatidylinositol 3-kinase (PI3K) and mitogen-activated protein kinase (MAPK) pathways was observed in H-38 cells and in Ishikawa endometrial cancer cells expressing GPR30; a similar effect was observed in JEG3 choriocarcinoma cells. STX treatment also increased cellular pools of phosphatidylinositol (3,4,5) triphosphate, a proposed ligand for the nuclear hormone receptor SF-1 (NR5A1). Consistent with these findings, STX, tamoxifen, and the phytoestrogen genistein were able to increase SF-1 transcription, promote Ishikawa cell proliferation, and induce the SF-1 target gene aromatase in a GPR30-dependent manner. Our findings suggest a novel signaling paradigm that is initiated by estrogen activation of the 7TM receptor GPR30, with signal transduction cascades (PI3K and MAPK) converging on nuclear hormone receptors (SF-1/LRH-1) to modulate their transcriptional output. We propose that this novel GPR30/SF-1 pathway increases local concentrations of estrogen, and together with classic ER signaling, mediate the proliferative effects of synthetic estrogens such as tamoxifen, in promoting endometriosis and endometrial cancers.
    Cancer Research 07/2009; 69(13):5415-23. · 9.28 Impact Factor
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    ABSTRACT: 3-Iodothyronamine is considered as a derivate of thyroid hormone as a result of enzymatic deiodination and decarboxylation. The physiological role of thyronamine (T1AM) is not known. The aim of this study was to analyze the metabolic response to T1AM in the Djungarian hamster Phodopus sungorus. We measured the influence of T1AM (50 mg/kg) on metabolic rate (VO(2)), body temperature (T (b)) and respiratory quotient (RQ) in this species and in BL/6 mice. T1AM treated hamsters as well as the mice showed a rapid decrease in VO(2) and T (b), accompanied by a reduction of RQ from normal values of about approximately 0.9 to approximately 0.70 for several hours. This indicates that carbohydrate utilisation is blocked by the injection of T1AM and that metabolic pathways are rerouted from carbohydrate to lipid utilisation in response to T1AM. This assumption was further supported by the observation that the treatment of T1AM caused ketonuria and a significant loss of body fat. Our results indicate that T1AM has the potential to control the balance between glucose and lipid utilisation in vivo.
    Journal of Comparative Physiology B 03/2008; 178(2):167-77. · 2.02 Impact Factor
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    ABSTRACT: 3-Iodothyronamine T1AM is a novel endogenous thyroid hormone derivative that activates the G protein-coupled receptor known as trace anime-associated receptor 1 (TAAR1). In the isolated working rat heart and in rat cardiomyocytes, T1AM produced a reversible, dose-dependent negative inotropic effect (e.g., 27+/-5, 51+/-3, and 65+/-2% decrease in cardiac output at 19, 25, and 38 microM concentration, respectively). An independent negative chronotropic effect was also observed. The hemodynamic effects of T1AM were remarkably increased in the presence of the tyrosine kinase inhibitor genistein, whereas they were attenuated in the presence of the tyrosine phosphatase inhibitor vanadate. No effect was produced by inhibitors of protein kinase A, protein kinase C, calcium-calmodulin kinase II, phosphatidylinositol-3-kinase, or MAP kinases. Tissue cAMP levels were unchanged. In rat ventricular tissue, Western blot experiments with antiphosphotyrosine antibodies showed reduced phosphorylation of microsomal and cytosolic proteins after perfusion with synthetic T1AM; reverse transcriptase-polymerase chain reaction experiments revealed the presence of transcripts for at least 5 TAAR subtypes; specific and saturable binding of [125I]T1AM was observed, with a dissociation constant in the low micromolar range (5 microM); and endogenous T1AM was detectable by tandem mass spectrometry. In conclusion, our findings provide evidence for the existence of a novel aminergic system modulating cardiac function.
    The FASEB Journal 06/2007; 21(7):1597-608. · 5.70 Impact Factor
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    ABSTRACT: Estrogens are involved in the hypothalamic control of multiple homeostatic functions including reproduction, stress responses, energy metabolism, sleep cycles, temperature regulation, and motivated behaviors. The critical role of 17beta-estradiol (E2) is evident in hypoestrogenic states (e.g., postmenopause) in which many of these functions go awry. The actions of E2 in the brain have been attributed to the activation of estrogen receptors alpha and beta through nuclear, cytoplasmic, or membrane actions. However, we have identified a putative membrane-associated estrogen receptor that is coupled to desensitization of GABAB and mu-opioid receptors in guinea pig and mouse hypothalamic proopiomelanocortin neurons. We have synthesized a new nonsteroidal compound, STX, which selectively targets the Galphaq-coupled phospholipase C-protein kinase C-protein kinase A pathway, and have established that STX is more potent than E2 in mediating this desensitization in an ICI 182, 780-sensitive manner in both guinea pig and mouse neurons. Both E2 and STX were fully efficacious in estrogen receptor alpha,beta knock-out mice. Moreover, in vivo treatment with STX, similar to E2, attenuated the weight gain in hypoestrogenic female guinea pigs. Therefore, this membrane-delimited signaling pathway plays a critical role in the control of energy homeostasis and may provide a novel therapeutic target for treatment of postmenopausal symptoms and eating disorders in females.
    Journal of Neuroscience 06/2006; 26(21):5649-55. · 6.91 Impact Factor
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    ABSTRACT: We have synthesized novel SERMs that activate a rapid response in CNS neurons, but which lack the ability to bind to the nuclear estrogen receptors (ERalpha and ERbeta). These compounds are analogues of 4-hydroxytamoxifen, but unlike 4-hydroxytamoxifen, they do not exist as a mixture of E/Z isomers. They contain a carboxamide insertion between the olefin and basic phenyl side chain, which results in more stable geometric isomers. The amide insertion also eliminates their ability to bind to the nuclear estrogen receptors, and hence, they are unable to modulate ER-mediated gene transcription as do classical estrogens and SERMs. We show that one of these analogues, ST-X, elicits a potent nongenomic estrogen response in the CNS by rapidly inhibiting GIRK activation in hypothalamic gamma-aminobutyric acid (GABA) and proopiomelanocortin (POMC) neurons. To our knowledge, ST-X is the only SERM that modulates rapid estrogen responses, but which lacks nuclear ER activity.
    ChemMedChem 06/2006; 1(5):565-71. · 2.84 Impact Factor
  • Frontiers in Neuroendocrinology - FRONT NEUROENDOCRINOL. 01/2006; 27(1):150-150.
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    ABSTRACT: Classically, 17beta-estradiol (E2) is thought to control homeostatic functions such as reproduction, stress responses, feeding, sleep cycles, temperature regulation, and motivated behaviors through transcriptional events. Although it is increasingly evident that E2 can also rapidly activate kinase pathways to have multiple downstream actions in CNS neurons, the receptor(s) and the signal transduction pathways involved have not been identified. We discovered that E2 can alter mu-opioid and GABA neurotransmission rapidly through nontranscriptional events in hypothalamic GABA, proopiomelanocortin (POMC), and dopamine neurons. Therefore, we examined the effects of E2 in these neurons using whole-cell recording techniques in ovariectomized female guinea pigs. E2 reduced rapidly the potency of the GABAB receptor agonist baclofen to activate G-protein-coupled, inwardly rectifying K+ channels in hypothalamic neurons. These effects were mimicked by the membrane impermeant E2-BSA and selective estrogen receptor modulators, including a new diphenylacrylamide compound, STX, that does not bind to intracellular estrogen receptors alpha or beta, suggesting that E2 acts through a unique membrane receptor. We characterized the coupling of this estrogen receptor to a Galpha(q)-mediated activation of phospholipase C, leading to the upregulation of protein kinase Cdelta and protein kinase A activity in these neurons. Moreover, using single-cell reverse transcription-PCR, we identified the critical transcripts, PKCdelta and its downstream target adenylyl cyclase VII, for rapid, novel signaling of E2 in GABA, POMC, and dopamine neurons. Therefore, this unique Gq-coupled estrogen receptor may be involved in rapid signaling in hypothalamic neurons that are critical for normal homeostatic functions.
    Journal of Neuroscience 11/2003; 23(29):9529-40. · 6.91 Impact Factor
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    Martha A. Bosch, Sandra C. Tobias

Publication Stats

492 Citations
33.66 Total Impact Points

Institutions

  • 2006–2008
    • University of California, San Francisco
      • Department of Pharmaceutical Chemistry
      San Francisco, California, United States
  • 2003–2006
    • Oregon Health and Science University
      • Department of Physiology & Pharmacology
      Portland, OR, United States