Guanosine Triphosphate-Binding Proteins
Enrique Pimentel in Handbook of Growth Factors, 2017
Interaction of the G protein with an activated receptor on the cell surface promotes the exchange of GDP, bound to the α subunit, for GTP and the subsequent dissociation of the α-GTP complex from the βτ heterodimer. A single receptor is capable of activating multiple G protein molecules, thus amplifying the ligand binding event. The α subunit with GTP bound and the free βτ unit interact with effectors that further amplify the signal. Such effectors include ion channels and enzymes (adenylyl cyclase, phospholipase C, phospholipase A2) that generate second messengers. Second messengers such as cAMP or inositol trisphosphate induce various intracellular changes, including protein phosphorylation, gene transcription, cytoskeletal reorganization, and alterations at the level of the plasma membrane including secretion and membrane depolarization. Termination of the signal generated by the receptor-activated G protein occurs when GTP bound by the α subunit of the G protein is hydrolyzed to GDP, and the α subunit then reassociates with the βτ complex (Figure 4.1).
Fetal and Neonatal Development of the Exocrine Pancreas
Jean Morisset, Travis E. Solomon in Growth of the Gastrointestinal Tract: Gastrointestinal Hormones and Growth Factors, 2017
Secretagogues such as CCK and carbachol act by first binding to specific receptors on the surface of the acinar cells. After binding, a series of events collectively termed “stimulus-secretion coupling” take place which finally result in secretion of enzymes from the acinar cells by exocytosis. Pancreatic exocrine secretion is stimulated by secretagogues that act primarily through either the adenylate cyclase system (secretin and vasoactive intestinal polypeptide) or the phosphatidylinositol pathway (CCK and cholinergic agents). The binding of cholecystoki-nin and cholinergic agents to their respective receptors results in the release of inositol trisphosphate and 1,2-diacylglycerol. Inositol trisphosphate induces calcium mobilization and activates calmodulin-dependent protein kinases. At the same time, 1,2-diacyglycerol activates and translocates protein kinase C from a cytosolic to a membraneous site. Taken together, protein kinase C activation, calcium mobilization and subsequent activation of calmodulin dependent protein kinase are viewed as important intermediary steps leading to secretion by the exocrine pancreas.32
Receptors for Neuropeptides: Receptor Isolation Studies and Molecular Biology
Edwin E. Daniel in Neuropeptide Function in the Gastrointestinal Tract, 2019
A class of receptors that can be readily expressed and detected at the level of a single oocyte are those receptors coupled in the cells normally expressing them to the phospholipase C pathway. The oocyte is endowed with such a receptor, i.e., the muscarinic acetylcholine receptor (see Figure 1). As in other systems muscarinic agonist binding leads to phospholipase C activation in the oocyte via a G protein. This results in polyphosphoinositide hydrolysis and formation of inositol trisphosphate, which acts as an intracellular second messenger to release calcium from the endoplasmic reticulum into the cytoplasm. Cytosolic calcium opens a calcium-operated chloride channel (see Figure 1), resulting in a strong depolarizing current that can be measured in a single oocyte by electrophysiological means.44–47 Alternatively, calcium mobilization can be assessed by [45Ca2+] efflux measurement in small groups of oocytes.48
Gastroparesis syndromes: emerging drug targets and potential therapeutic opportunities
Published in Expert Opinion on Investigational Drugs, 2023
Le Yu Naing, Matthew Heckroth, Prateek Mathur, Thomas L Abell
Substance P is a neuropeptide in the tachykinin peptide family that plays a role in various processes throughout the body, including pain perception and inflammation. Substance P’s receptor, neurokinin type 1 (NK-1 R), is a transmembrane bound receptor located on many cell types including GI vagal afferents and CNS areas involved in the vomiting reflex. It is a G-protein linked receptor that acts through both the inositol trisphosphate/diacylglycerol (IP3/DAG) and cAMP second messenger systems, depending on cell type. The binding of Substance P to NK-1 R in the area postrema and nucleus tractus solitarius triggers emesis. Additionally, in the GI tract, enteric motor neurons release both acetylcholine and substance P onto smooth muscle. Recent animal studies suggest that Substance P, via the NK-1 R, also acts as a co-neurotransmitter important for maintaining muscular responsiveness to acetylcholine and regulating gastric motility[34].
Short-term effects of metformin and myo-inositol in women with polycystic ovarian syndrome (PCOS): a meta-analysis of randomized clinical trials
Published in Gynecological Endocrinology, 2019
Fabio Facchinetti, Beatrice Orrù, Giovanni Grandi, Vittorio Unfer
MI is one of the nine stereoisomers of inositol, a physiological compound belonging to the sugar family, contained in foods such as legumes, nuts, fruits, whole grains. Furthermore, it is synthesized endogenously from glucose 6-phosphate [40, 41], and it is found at the level of cell membranes in the form of phosphatidylinositol, bound to membrane phospholipids. MI is the most abundant form among inositol(s) family, accounting for about 99% of the intracellular inositol in ovaries and testis [42, 43]. Its effect starts when it is incorporated into cell membranes as phosphatidyl-MI, the precursor of inositol triphosphate that acts as second messenger regulating the activities of several hormones such as thyroid-stimulating hormone, stimulating follicle hormone, and insulin, improving their signals [44, 45]. MI has been shown to improve insulin sensitivity and oocyte quality, to reduce hyperandrogenism and regulate menstrual cycles ovulation and hirsutism [10, 46].
Emerging therapeutic targets for retinoblastoma
Published in Expert Opinion on Therapeutic Targets, 2022
Radhika Manukonda, Revu VL Narayana, Swathi Kaliki, Dilip K Mishra, Geeta K Vemuganti
Ca2+ is an abundant intracellular molecule that acts as a second messenger that regulates cell proliferation, gene transcription, and apoptosis. Intracellular calcium homeostasis is critical for cell survival. Any alteration in its equilibrium affects molecular factors and signaling pathways such as Ca2+ channels, transporters, calcium-binding proteins, and Ca2+- adenosine triphosphate (ATP)ases. Altered intracellular calcium levels and signaling pathways cause invasion, tumor metastasis, and favor cell survival [23]. Different research groups have studied the involvement of Ca2+-dependent molecular pathways in Rb tumor progression. Kim et al. elucidated the molecular mechanism of calcium mobilization in human Rb. Intracellular calcium molecules from the internally stored deposits are carried out through the inositol triphosphate (IP3)-dependent pathway via activating M3/M5 muscarinic receptors in the undifferentiated Rb cells [24]. Mergler et al. reported that neoplastic properties in Rb are attributed to Ca2+-dependent signaling pathways. The sensitivity of clinical drug etoposide can be enhanced via upregulation of transient receptor potential cation channel gene expression in etoposide-resistant Wills Eye Research Institute-Retinoblastoma-1 (WERI-Rb1) cells [25]. The above reports suggest that Ca2+ channels/transporters and pumps can serve as potential therapeutic targets of Rb.
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