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Endocrine Therapies
Published in David E. Thurston, Ilona Pysz, Chemistry and Pharmacology of Anticancer Drugs, 2021
After secretion into the bloodstream, GnRH travels via the portal blood to the pituitary gland where it acts on its own receptor known as the Gonadotropin-Releasing Hormone Receptor (GnRHR), a seven-transmembrane G-Protein-Coupled receptor (Figure 8.24). This stimulates production of the beta-isoform of Phosphoinositide Phospholipase C, which then mobilizes calcium and Protein Kinase C. This results in the activation of proteins involved in the synthesis and secretion of the two pituitary hormones, Luteinizing Hormone and Follicle-Stimulating Hormone from the anterior pituitary. These hormones induce the production of estrogen and progesterone in the ovaries in females, and testosterone in the testes in males. This, in turn, induces ovulation in females and gametogenesis in males. GnRH is the target of various regulatory processes within the hypothalamic–pituitary–gonadal axis, and is inhibited by rising levels of estrogen or testosterone in females and males, respectively (i.e., via a feedback loop).
Leukotriene Receptors in the Airways
Published in Devendra K. Agrawal, Robert G. Townley, Inflammatory Cells and Mediators in Bronchial Asthma, 2020
John B. Cheng, James F. Eggler
However, two major differences have been noticed in the signal transduction pathways of LTD4 and LTB4 receptors in differentiated U-937 cells. The LTB4 receptor appears to couple exclusively to pertussis toxin-sensitive Gi protein, whereas part of the biological response by LTD4 in these cells is not sensitive to pertussis toxin treatment. It appears that the LTD4 receptor is coupled to an additional G-protein which is a phosphoinositide phospholipase C-selective, GTP-sensitive protein.63,73,74,85 In addition, unlike LTB4, which initiates a transient decrease in intracellular pH (acidification) of HL-60 cells followed by a prolonged alkalization, LTD4 causes only an alkalization of cytoplasm.85
Diverse Receptors and G Proteins Control the Generation of cAMP, Inositol Phosphates, and Tension in the Myometrium
Published in Robert E. Garfield, Thomas N. Tabb, Control of Uterine Contractility, 2019
Simone Harbon, Lien Do Khac, Zahra Tanfin, Olivier Goureau, Denis Leiber
In the myometrium, as in many other smooth muscles, Ca2+ and cAMP, the two major intracellular second messengers, exert opposite effects at the level of contractility. The necessity of calcium for smooth muscle contraction has long been recognized. This role of Ca2+ is obligatory, whether the stimulus is of hormonal nature or is voltage-induced. The increase in intracellular Ca2+ evoked by stimulatory agonists is considered to originate at least in part from intracellular stores.1–3 In this regard, the phosphoinositide-phospholipase C transducing mechanism that is consistently associated with Ca2+-mobilizing receptors4,5 has been demonstrated to be activated by contracting agonists in different myometrial preparations.6–9 Additionally, a number of recently reported findings provide satisfactory correlations between the increased generation of inositol phosphates, the ability of inositol 1,4,5-trisphosphate, InsP(1, 4,5,)P3, to release Ca2+ from intracellular stores, and the accompanying Ca2+-induced uterine contractions.7,10,11
Triggering receptor expressed on myeloid cells-1 (TREM-1) as a therapeutic target in infectious and noninfectious disease: a critical review
Published in International Reviews of Immunology, 2020
Pedro Henrique dos Santos Dantas, Amanda de Oliveira Matos, Ernandes da Silva Filho, Marcelle Silva-Sales, Helioswilton Sales-Campos
As mentioned above, mTREM-1 activity depends on DAP12 for activation and intracellular signaling [14] (Figure 1). After activation, ITAM motifs are phosphorylated by Src kinases [39,40]. Then, these domains anchor zeta-chain-associated protein kinase 70 (ZAP70) and spleen tyrosine kinase (SYK) [40]. After that, SYK phosphorylates casitas b-lineage lymphoma (CBL), son of sevenless protein (SOS) and growth factor receptor binding protein-2 (GRB2), leading to the activation of Jakus kinase (JAK), Extracellular signal-regulated kinases (ERK), Phosphoinositide 3-kinase (PI3K) and Phosphoinositide phospholipase C gamma (PLCγ) pathways [41](Figure 1). These pathways activate the transcription factors Elk-1, NFAT, AP1, c-Fos, c-Jun, STAT3/STAT5 and NF-κB, all involved in the production of inflammatory mediators such as IL-6, IL-8, IL-1β and TNF-α (Figure 1), besides inducing calcium mobilization and changes in the actin cytoskeleton [42]. The activation of mTREM-1 also inhibits pro-apoptotic molecules (BID, BAD and BAX) and the release of cytochrome C by mitochondria, thus maintaining mitochondrial integrity and prolonged cell survival [5,35].