Regulation of the Arachidonic Acid Cascade and PAF Metabolism in Reproductive Tissues
Murray D. Mitchell in Eicosanoids in Reproduction, 2020
Glycerophospholipid degradation in mammalian tissue is primarily catalyzed by the action of phospholipases, as illustrated in Figure 2. With the exception of phosphatidylinositol, most glycerophospholipids are degraded via phospholipase A enzymes. The phosphatidylinositol pathway employs phospholipase C; the products of this reaction are inositol phosphate(s) and diacylglycerol. The role of the inositol polyphosphates and diacylglycerol as second messengers and the relationship of Ca2+ to signal transduction and protein kinase C activity have recently been reviewed.31,32 More recently, a role for phospholipase D, which has been purified from mammalian tissues,33 has been implicated in the generation of phosphatidic acid, which may subsequently function as a second messenger.34
Answers
Calver Pang, Ibraz Hussain, John Mayberry in Pre-Clinical Medicine, 2017
This question focuses on effector mechanisms in intracellular signalling, particularly second messengers. Some important generating effects include adenylyl cyclase and phospholipase C. Adenylyl cyclase is a plasma membrane protein that can be activated (via Gs) or inhibited (via Gi) by activation of different receptors. This enzyme hydrolyses cellular ATP to produce cyclic AMP, which interacts with protein kinase A therefore phosphorylating other proteins and their subsequent effects. Phospholipase C involves the hydrolysis of PIP2 to generate IP3 and DAG. IP3 interacts with intracellular receptors on the endoplasmic reticulum to allow efflux of Ca2+ into the cytoplasm. DAG interacts with protein kinase C causing protein phosphorylation.
Adrenergic Agonists
Sahab Uddin, Rashid Mamunur in Advances in Neuropharmacology, 2020
α1 adrenergic receptors (Fig. 3.3) can be seen predominantly distributed in the smooth muscles (of the blood vessels, genitourinary system, and intestine) (Walden et al., 1997), liver, heart, and the salivary gland. These are brought about by stimulating Gq or G0 signaling mediators. The enzyme phospholipase C is activated by Gq thereby activating the second messengers such as IP3/DAG. α1A receptor works by activating calcium ion channels whereas α1B receptor acts by exerting its activity on IP3 which potentiates influx of Ca2+ ions mediating vascular and genitourinary smooth muscle contractions which are probably by activating Ca2+-troponin complex causing increased myocardial contraction. DAG produces activation of the inactive Protein Kinase C. The probable mechanism for relaxation of intestinal smooth muscles and K+ release from salivary glands may be due to G0 signaling mediator stimulation. α1a is the recombinant of receptor α1A. In some blood vessels, the vasoconstriction response is brought about by α1B adrenoceptor which is involved in the heart and blood pressure functioning. The α1B as well α1a adrenoceptors both play a vital function in memory and the nociceptive responses (Han et al., 1990; Muramatsu, 1995; Tanoue et al., 2002).
CCR5 is a potential therapeutic target for cancer
Published in Expert Opinion on Therapeutic Targets, 2021
Hossein Hemmatazad, Martin D. Berger
Upon ligand binding, CCR5 undergoes a conformational change with subsequent release of the αi and βγ G-protein subunits to allow downstream signaling [41]. The Gβγ protein subunits stimulate phospholipase C, which induces a catalytic reaction, resulting in the depletion of phosphatidylinositol 4,5-bisphosphate (PIP2) while generating inositol-1-4,5-triphosphate (IP3) and diacylglycerol (DAG). IP3 binds to calcium channels located in the endoplasmic reticulum and thereby induces the release of Ca2+ with subsequent increase in cytosolic Ca2+. Increased levels of both DAG and Ca2+ activate protein kinase C (PKC), a key player in several biological processes such as cell cycle regulation and T cell activation [23,42]. CCR5-induced downstream signaling includes activation of the JAK/STAT and the PI3K/AKT pathways [43].
Bruton’s tyrosine kinase as a promising therapeutic target for multiple sclerosis
Published in Expert Opinion on Therapeutic Targets, 2023
Darius Saberi, Anastasia Geladaris, Sarah Dybowski, Martin S. Weber
After antigen binding to the B cell receptor (BCR), Lck/Yes novel tyrosine kinase (Lyn), a member of the SRC kinase family phosphorylates the Igα and Igβ immunoreceptor tyrosine-based activation motifs (ITAMs), which then binds spleen tyrosine kinase (SYK). In the next step, SYK gets phosphorylated by Lyn and BTK is recruited from the cytosol to the plasma membrane [75]. In general, activation of BTK is characterized by phosphorylation at the position Y551 of BTK. This promotes the catalytic activity of BTK and subsequently results in its autophosphorylation at the position Y223 in its SH3 domain [71]. Active BTK phosphorylates phospholipase C gamma 2 (PLCγ2). Consequently, PLCγ2 generates two second messengers, inositol 1,4,5-triphosphate (IP3) and diacylglycerol (DAG). The activation of calcium channels by IP3 results in a transport of nuclear factor of activated T cells (NFAT) into the nucleus. The pathway of nuclear factor ‘kappa-light-chain-enhancer’ (NF-κB) of activated B cells and mitogen-associated protein kinase (MAPK) is activated by DAG. The expression of several genes that are essential for B cell survival and proliferation chemokine and cytokine expression is regulated by NFAT and NF-κB (Figure 1). In summary, this complex cascade leads to an increase in survival and accelerates the proliferation of B cells, and therefore highlights the pivotal role of BTK in B cells [76].
Treatment of small (T1mic, T1a, and T1b) node-negative HER2+ breast cancer – a review of current evidence for and against the use of anti-HER2 treatment regimens
Published in Expert Review of Anticancer Therapy, 2022
Kai CC Johnson, Dionisia Quiroga, Preeti Sudheendra, Robert Wesolowski
Proto-oncoprotein HER2/neu (ERBB2) is a cell surface receptor that belongs to the epidermal growth factor receptor (EGFR) family of co-receptors. HER2 has an extracellular domain, transmembrane domain, and intracellular domain with tyrosine kinase activity. Activation of HER2 has been implicated in cell proliferation, suppression of apoptosis, and angiogenesis [1–3]. This occurs as a result of homo- or hetero-dimer formation with another HER2 receptor or another member of the receptor factor family (i.e. EGFR, HER3, and HER4), autophosphorylation, and activation of the tyrosine kinase domain. This action leads to downstream activation of several signaling pathways, including phosphoinositide 3-kinase (PI3K), mitogen-activated protein kinase (MAPK), signal transducer and activator of transcription (STAT), phospholipase C γ, and protein kinase C [1–3]. The HER2 receptor is typically expressed on the surface of cells in the gastrointestinal tract, lungs, myocardium, endometrium, ovaries, and breasts [4–6]. HER2 gene amplification occurs in approximately 20–25% of breast cancers. As a result of this amplification, there is at least a 2-log increase in the number of HER2 receptors present on the cell surface, often to the point where HER2 receptor homodimers form spontaneously, allowing for autophosphorylation and activation [7]. This results in increased expression of genes important for cell growth, cell division, invasion, and metastases, leading to an aggressive form of breast cancer that, historically, has been associated with worsened survival outcomes both in the operable and metastatic settings [8–11].
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