Overview of Mechanisms for Coupling of Receptor-Agonist Interactions With Physiological Effects
John C. Matthews in Fundamentals of Receptor, Enzyme, and Transport Kinetics, 2017
The activity of the adenylate cyclase enzyme is regulated by a receptor on the outside of the cell membrane through an intervening G protein. When the agonist binds to its receptor the stimulated receptor-agonist complex causes the G protein to exchange its bound GDP molecule for a molecule of GTP from inside the cell. The G protein-GTP complex, in turn, interacts with the adenylate cyclase to activate it. The G protein, which is a GTPase enzyme, then hydrolyzes the GTP to GDP. This terminates the ability of the G protein to activate adenylate cyclase. Meanwhile, cyclic nucleotide phosphodiesterase enzymes and protein phosphatase enzymes in the cell function to reverse the effects of the underlying receptor stimulation. They do so by converting cyclic AMP to AMP and by removing the phosphate groups from the phosphorylated proteins. As was true with the nicotinic acetyl choline receptor, the extracellular agonist will only be available to interact with its receptor for a short period of time. In addition to enzymatic degradation of the agonist, several cellular uptake processes are important for rapidly clearing receptor agonists from the extracellular space as a means of terminating receptor stimulation.
Cyclic Nucleotide Metabolism and Action During Senescence
Richard C. Adelman, George S. Roth in Endocrine and Neuroendocrine Mechanisms of Aging, 2017
Evaluating changes in cyclic nucleotide phosphodiesterase activity, whether measured as total activity or activity at physiological substrate concentration (<1 μΜ), is somewhat more complicated than assessing cyclase activities. In most mammalian tissues three or more forms of phodphodiesterase have been described, each differing both in kinetic properties and subcellular distribution (for reviews see Appleman et al.53 and Wells and Hardman54). Because of substantial differences in Vmax and Km of the different forms, maximal, total activity for a tissue may be attained only at very high, unphysiological substrate concentrations, while measurements at low substrate concentrations may be a composite of activities of the different forms determined by their relative, tissue-specific levels. Consequently, a first approach in assessing activities in homogenates or in subcellular fractions must entail assay conditions that take advantage of the differences in regulatory properties or subcellular distribution of the multiple forms, thus achieving at least some discrimination in relative activity levels. Suggestions of age-related changes might then be examined further using one or more separation techniques (anion-exchange chromotography, gel filtration, isoelectric focusing, Polyacrylamide gel electrophoresis, sucrose density-gradient centrifugation, affinity column chromatography) under conditions in which quantitative recoveries can be obtained.
Role of Steroids in the Onset of Labor
Robert E. Garfield, Thomas N. Tabb in Control of Uterine Contractility, 2019
So far, the presence of a single or of two isoform(s) of PDE according to species and/or techniques of purification were reported. Recently, four soluble PDE isozymes have been isolated and characterized from pregnant and nonpregnant human myometrium.69 On the basis of the potencies of classical selective modulators of PDEs, a calcium-calmodulin-sensitive PDE (CaM-PDE), a cGMP-stimulated PDE (cGS-PDE), a cGMP-inhibited PDE (cGi-PDE), and a cAMP-specific PDE (rolipram sensitive or ROI-PDE) were identified. CaM-PDE, an integrating agent between both second messengers—calcium and cyclic nucleotides—is the major form present in the nonpregnant myometrium. During the second half of human pregnancy, the ROI-PDE isoform is the most abundant myometrial PDE. The abundance near term of this isoform, which exhibits a high affinity for cAMP, could help the myometrium to get ready to develop important contractile activity during the parturition process. Rolipram, the selective inhibitor of the ROI-PDE isoform, is a potent relaxant of the isolated pregnant human and guinea pig myometrium.70 It may thus be surmised that the cyclic nucleotide phosphodiesterase activity could be regulated by steroid changes during pregnancy, but decisive proofs are still lacking.
The Wnt/β-catenin pathway in breast cancer therapy: a pre-clinical perspective of its targeting for clinical translation
Published in Expert Review of Anticancer Therapy, 2022
Dezaree Raut, Amisha Vora, Lokesh Kumar Bhatt
The non-canonical Wnt signaling pathway, also known as the β-catenin-independent pathway, is divided into the Wnt/Ca2+ pathway and planar cell polarity (PCP) pathway. In the Wnt/Ca2+ pathway, when Wnt binds to the frizzled (Fz) receptor, it causes intracellular binding of Dvl near the Fz receptor (FZD). In addition to Dvl, the Fz receptor also stimulated trimeric G-protein. Simultaneous stimulation of Dvl and D-protein can activate either Phospholipase (PLC) or Cyclic nucleotide phosphodiesterase (PDE). When PLC is activated, it causes activation of Inositol trisphosphate (IP3). IP3 causes an intracellular release of calcium which further causes calcineurin and CaMK11 activation. CaMK11 activates a nuclear factor of activated T-cells, responsible for cell adhesion, migrations, and tissue separation. On the other hand, calcineurin activates certain substances that interfere with the canonical Wnt signaling pathway to regulate dorsal axis formation negatively. If PDE gets activated, it causes inhibition of calcium release from ER. This pathway helps to regulate intracellular calcium levels by controlling the calcium release from the endoplasmic reticulum [16].
Asthma pharmacotherapy: an update on leukotriene treatments
Published in Expert Review of Respiratory Medicine, 2019
Hoang Kim Tu Trinh, So-Hee Lee, Thi Bich Tra Cao, Hae-Sim Park
Three LTRAs (montelukast, pranlukast and zafirlukast) are approved and listed in current treatment guidelines for asthma treatment. They are known to be potent, selective and competitive antagonists to CysLTR1, in which montelukast showed the highest binding affinity [12]. Recent studies demonstrated that these drugs can modulate diverse pathways aside from CysLTR1 antagonism, including cyclic nucleotide phosphodiesterase, 5-LO, nuclear factor kβ and microsomal prostaglandin (PG) E2 synthase-1 [12,13]. In addition, it is well tolerated in a broad-dose range and is administered in clinical trials for elderly asthmatics [14], patients with aspirin-exacerbated respiratory disease (AERD) [15] and smoker asthmatics [16]. Patients taking montelukast showed reduced risk of recurrent strokes (HR = 0.62, 95% CI, 0.38–0.99) and were associated with lower levels of biomarkers for cardiovascular disease [17,18], suggesting the potential effectiveness of montelukast in asthmatic patients with multimorbid conditions.
Anti-trypanosomatid structure-based drug design – lessons learned from targeting the folate pathway
Published in Expert Opinion on Drug Discovery, 2022
Joanna Panecka-Hofman, Ina Poehner, Rebecca C. Wade
Therefore, even in the best-controlled case of sleeping sickness, better treatments, that overcome resistance and have reduced side effects, are needed. Unfortunately, drug design efforts against trypanosomiases are not generally profitable for pharmaceutical companies, since these so-called ‘neglected diseases’ occur mostly in poor regions of the world [21]. However, in recent years, there have been several initiatives to advance drug design against neglected tropical diseases. These include (i) the Drugs for Neglected Diseases initiative (DNDi, https://dndi.org [22]), (ii) the Trypanogen and Trypanogen+ projects funded by AAS/Wellcome under the H3Africa initiative (http://trypanogen.net/ [23]), (iii) two EU-funded projects that focused on targeting specific biochemical pathways of parasites causing the diseases: New Medicines for Trypanosomatidic Infections (NMTrypI [24], https://fp7-nmtrypi.eu/ [25], https://cordis.europa.eu/project/id/603240 [26]) and Parasite-specific cyclic nucleotide phosphodiesterase inhibitors to target Neglected Parasitic Diseases (PDE4NPD, https://cordis.europa.eu/project/id/602666 [27]). One of the focuses of the NMTrypI project, in which the authors of the present article participated, was targeting the parasite folate pathways. We here review recent efforts in anti-trypanosomatid structure-based drug design (SBDD) from this perspective.
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