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Endocardial Endothelial Modulation of Myocardial Contraction
Published in Malcolm J. Lewis, Ajay M. Shah, Endothelial Modulation of Cardiac Function, 2020
Stanislas U. Sys, Puneet Mohan, Luc J. Andries, Gilles De Keulenaer, Paul F. Fransen, Dirk L. Brutsaert
The mechanism(s) as to how basal NO-cGMP mediate the positive inotropic effect is still speculative. Shah et al. (1994) observed that perfusion of isolated myocytes with 8-bromo cGMP (50 mmol/L) had, in 50% of the cells, an initial transient positive inotropic effect which was associated with an increase in cytosolic Ca++. Electrophysiological evidence has suggested that a cGMP-inhibitable cAMP-phosphodiesterase, known to be present in the heart, may underlie the cGMP-mediated positive inotropic effect by increasing sarcolemmal Ca++ influx and thereby Ca++ availability during subsequent contraction (Méry et al., 1993). A PKG-mediated phosphorylation of calcium slow channels was suggested, in skeletal muscle, to explain a cGMP-induced stimulation of calcium slow channels (Kokate, Heiny and Sperelakis, 1993). The response to cGMP could also be mediated by the recently described second messenger, cyclic ADP ribose (cADPR), which stimulates release of Ca++from intracellular stores through the ryanodine receptor. It has been reported that cADPR increases the open probability of cardiac ryanodine-sensitive Ca++ channels to trigger the release of Ca++ from the sarcoplasmic reticulum in cardiac cells (Mészáros, Bak and Chu, 1993). Thus, irrespective of the mechanism, an increase in intracellular Ca++ may underlie the cGMP-mediated positive inotropic effect.
Ion Channels in Immune Cells
Published in Shyam S. Bansal, Immune Cells, Inflammation, and Cardiovascular Diseases, 2022
Devasena Ponnalagu, Shridhar Sanghvi, Shyam S. Bansal, Harpreet Singh
TRP channels are present in both the adaptive and the innate immune cells and act as mediators to conduct Ca2+, Mg2+ (TRPM2, TRPM6, TRPM7), and Na+ (TRPM4). As described earlier, the major role of some of the TRP channels is to modulate intracellular Ca2+ in immune cells and, thus, influence their function. They have been established to play a role in phagocytosis, immune cell migration, and the release of inflammatory cytokines. It is known that, following TCR stimulation, TRPM2 channels become activated probably via release of cyclic ADP ribose (ADPR) from the ER, which is involved in their proliferation and pro-inflammatory cytokine secretion59,60. Moreover, TRPM2 deficiency mitigated the development of encephalomyelitis in mice61. TRPM2-mediated Ca2+ signaling was also shown to be involved in the maturation of DCs through modulation of the processing of MHC class II molecules62. The absence of TRPM4 channels in DCs led to impaired migration due to disruption of Ca2+ homeostasis60. In addition, phagocytic activity and cytokine release by macrophages were diminished in TRPM4-deficient mice60. B cells lacking a TRPM7 channel exhibited an inability to proliferate and an increased death rate60. In the case of T cells as well, mice lacking T cell–specific TRPM7 showed a defect in T cell development60. There are also other members of this channel group that have been studied extensively and shown to be important in modulating immune cell function and development and inflammatory diseases60. Due to their key role in immune cell maturation and activation, they are also considered to be a great therapeutic target against autoimmune disorders, like rheumatoid arthritis, type I diabetes, lupus erythematosus, and multiple sclerosis, and thus need to be evaluated clinically.
Noninsulin-Dependent Animal Models of Diabetes Mellitus
Published in John H. McNeill, Experimental Models of Diabetes, 2018
Christopher H. S. McIntosh, Raymond A. Pederson
What other sites could be involved in altered insulin secretion? There have been a number of suggestions. There is an overall decrease in islet mitochondrial DNA content, but no major deletions or restriction fragment polymorphisms,324 and it was suggested that reduced levels may occur as a consequence of the disturbed metabolic environment. Roles for reductions in ADP-ribosyl cyclase activity and intracellular cyclic ADP-ribose levels,325and reduced expression of a Ca2+-ATPase, SERCA-3, which is involved in the active uptake of cytosolic Ca2+ into the endoplasmic reticulum, have also been reported.326 Additionally, Leckstrom et al.327 showed that the plasma islet amyloid polypeptide (IAPP)/insulin ratio was higher in GK rats after glucose injection, equivalent to a relative hypersecretion of IAPP. Increased amounts of islet IGF II mRNA and a high-molecular-weight IGF II peptide were found in the 2- and 6-month-old GK rats compared with 1-month-old rats.328 The authors suggested that it could have resulted in the development of fibrosis, and the Nidd/gk1 region of rat chromosome 1, identified by Gauguier et al.303 as a susceptibility locus, contains the IGF II gene. The hyperglycemic-hyperinsulinemic pattern observed in GK rats is also associated with hepatic glucose overproduction, decreased responsiveness to insulin in the basal state, and moderate insulin resistance in muscles and adipose tissues, present by 8 weeks of age in GK females. The origin of insulin resistance has been associated with decreased receptor number.329 However, there is probably also a deficiency in the signal-transduction pathways. Farese et al.330 suggested that diabetic GK rats have a defect in synthesizing or releasing functional chiro-inositol-containing inositol phosphoglycan in adipocytes, and that defective IPG-regulated intracellular glucose metabolism contributes to insulin resistance.
Microvesicles expressing adenosinergic ectoenzymes and their potential role in modulating bone marrow infiltration by neuroblastoma cells
Published in OncoImmunology, 2019
Fabio Morandi, Danilo Marimpietri, Alberto L. Horenstein, Maria Valeria Corrias, Fabio Malavasi
Metastatic NB cells in the BM exploit different mechanisms to escape the control of the immune system. The most known are downregulation of HLA molecules along with the expression and/or release of inhibitory molecules (i.e., HLA-G, MICA, B7H3 and calprotectin among the others.9,12,13 However, one of the strategies adopted by different human tumors [i.e. breast cancer,14 melanoma,15,16 prostate cancer,17 and gastric carcinom18] to impair the anti-tumor immune response relays on the local production of the immunosuppressive adenosine (ADO). Extracellular ADO is generated by a set of adenosinergic ectoenzymes, ruling the classical (the first to be identified) and alternative pathways. The first one relies on the metabolism of adenosine 5ʹ-triphosphate (ATP), metabolized by CD39, an ecto-nucleoside-triphosphate-diphosphohydrolase. ATP is converted to adenosine 5ʹ-diphospate (ADP), and the latter molecule into adenosine 5ʹ-monophospate (AMP).19 The alternative pathway starts from the metabolism of nicotinamide adenine dinucleotide (NAD+) operated by CD38, an ectoenzyme with ADP-ribosyl-cyclase/cyclic ADP ribose-hydrolase enzymatic activities, that converts NAD+ to adenosine diphosphate ribose (ADPR).20 The latter molecule may be converted to AMP in the presence of CD203a(PC-1) (an ectonucleotide-pyrophosphatase-phosphodiesterase-1). The same enzyme can also convert ATP to AMP. The two pathways converge to the action of CD73, a 5ʹ-nucleotidase, which converts AMP to AD.21,22
CD38 as an immunotherapeutic target in multiple myeloma
Published in Expert Opinion on Biological Therapy, 2018
Francesca Bonello, Mattia D’Agostino, Maria Moscvin, Chiara Cerrato, Mario Boccadoro, Francesca Gay
Next to its receptor function, CD38 was recently described as part of the leukocyte ectonucleotidases family, characterized by two main substrates: nicotinamide adenine dinucleotide (NAD+) and nicotinamide adenine dinucleotide phosphate (NADP+). CD38 converts NAD+ to ADP ribose (ADPR) directly (hydrolase activity) or through formation and degradation of cyclic ADP ribose to ADPR (cyclase activity). Furthermore, in acidic conditions, CD38 catalyzes the generation of nicotinic acid-adenine dinucleotide phosphate (NAADP) from NADP+. Overall, the final result of these catalytic reactions is the generation of potent intracellular Ca2+ mobilizing compounds (cADPR, ADPR, and NAADP) followed by activation of signaling pathways that control various biological processes, such as lymphocyte proliferation [19]. Interestingly, recent studies suggest a pivotal role for CD38 involved in the production of adenosine, which has immunosuppressive effects [20]. Thus, this enzyme is suggested to function as an ‘immunological switch’ capable of converting a proinflammatory extracellular environment into an adenosine-rich, anti-inflammatory niche, suppressing antitumor immunity and promoting tumor progression.
Artificial oocyte activation: physiological, pathophysiological and ethical aspects
Published in Systems Biology in Reproductive Medicine, 2019
George Anifandis, Alexandros Michopoulos, Alexandros Daponte, Katerina Chatzimeletiou, Mara Simopoulou, Christina I. Messini, Nikolas P. Polyzos, Katerina Vassiou, Konstantinos Dafopoulos, Dimitrios G. Goulis
In most species, the Ca+2 increases during fertilization are predominately caused by IP3-mediated Ca+2 release from the endoplasmic reticulum. Apart from IP3, additional agents, such as cyclic GMP (cGMP), cyclic ADP-ribose (cADP ribose), nicotinic acid adenine dinucleotide phosphate (NADP) and nitric oxide (NO) can also cause Ca+2 release (Whalley et al. 1992; Galione 1994; Galione and Churchill 2000; Willmott et al. 2000). It is possible that the primary role of IP3 as an initiator of intracellular Ca+2 release during fertilization is accompanied by the supporting action of these additional agents to regulate the increases in Ca +2 (Jaffe 1993).