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Regulation of Growth of Airway Smooth Muscle by Second Messenger Systems
Published in Alastair G. Stewart, AIRWAY WALL REMODELLING in ASTHMA, 2020
More recent studies suggest that the levels of Ca2+ remaining in Ca2+-accumulating organelles may also have important consequences for signaling and growth regulation.90,91 Depletion of calcium stores within the endoplasmic reticulum by thapsigargin markedly inhibited growth factor–induced mitogenesis in a transformed smooth muscle cell line.90 Such effects may result from either an altered ability of the endoplasmic reticulum to generate specific Ca2+ signals necessary for cell growth or a modulation of key endoplasmic reticulum functions that are dependent on intraluminal Ca2+ to induce mitogenesis. Interestingly, the effects of thapsigargin on cell growth were independent of any observed effects on PKC activation.90 Taken together, current evidence suggests that cytosolic Ca2+ mobilization or depletion of Ca2+ stores in response to growth factors may be critical to modulate cell proliferation in some cells.
Artemisinins
Published in M. Lindsay Grayson, Sara E. Cosgrove, Suzanne M. Crowe, M. Lindsay Grayson, William Hope, James S. McCarthy, John Mills, Johan W. Mouton, David L. Paterson, Kucers’ The Use of Antibiotics, 2017
Kamala Thriemer, Julie A. Simpson, James S. McCarthy, Ric N. Price
An alternate hypothesis for the mechanism of action of the artemisinins proposes a role for artemisinin interfering with calcium homeostasis in the parasite cytoplasm (Krishna et al., 2006). Homologs of the sarcoplasmic-endoplasmic reticulum Ca2+−adenosine triphosphatases (ATPases) (SERCA) have been identified in P. falciparum (Kimura et al., 1993) and are expressed at different stages of the life cycle (Krishna et al., 2001b). When expressed in Xenopus oocytes, PfATP6 is inhibited by artemisinins but not by other antimalarials (Eckstein-Ludwig et al., 2003). Furthermore, thapsigargin, which shares chemical similarities with artemisinin, is a potent and selective inhibitor of SERCA. In cross-competition studies, thapsigargin demonstrates antagonistic antiparasitic activity with artemisinin, consistent with a common mode of action (Eckstein-Ludwig et al., 2003). However, more recent work contradicted the notion of SERCA inhibition, and no antagonism between thapsigargin and artemisinin was reported (del Pilar Crespo et al., 2008).
Neurotrophic Action of VIP
Published in Sami I. Said, Proinflammatory and Antiinflammatory Peptides, 2020
Douglas E. Brenneman, Joanna M. Hill, Pierre Gressens, Illana Gozes
Previous studies indicated that the survival of postmitotic neurons in CNS cultures could be increased by a subnanomolar concentration of VIP. Therefore, one would predict from this pharmacological response that survival-promoting actions of VIP might involve a receptor and signal transduction mechanism that are unique, probably not involving cAMP-dependent phosphorylations, the conventional and accepted pathway for VIP’s second messenger signal. Several lines of evidence indicate that VIP-mediated increases in neuronal survival and astroglial secretion are mediated through a calcium-dependent, protein kinase C-activated pathway. The first indication of a non-cAMP mechanism was from the great mismatch in EC50’s for survival promotion (30 pM) (2) versus that of VIP-mediated increases in cAMP (3 μM) (22). This 100,000-fold difference in effective concentrations strongly suggested an alternative mechanism, an idea sustained by ensuing studies. In cultured astroglia cells, Fatatis and co-workers found that subnanomolar amounts of VIP elicited mobilization of intracellular calcium (23). This group found that one in five astrocytes responded by calcium increases after VIP treatment. The increase in calcium was apparently from an intracellular compartment, because the response to VIP persisted in the absence of extracellular calcium. Furthermore, thapsigargin pretreatment, which depletes intracellular calcium stores, abolished the VIP-induced calcium response. The VIP-elicited increases were accompanied by acute (1 min) and transient elevations of inositol triphosphate. Subsequent investigations indicated that subnanomolar VIP treatment resulted in the translocation of protein kinase C (PKC) from the cytoplasm to the nucleus (24). Examination of specific PKC isotypes by Western blot analysis showed that VIP treatment produced a marked increase in nuclear PKC-alpha and, to a lesser extent, PKC-delta and -zeta immunoreactivity. Although cAMP may not be involved in the secretion of survival-promoting substances from astroglia, this relationship may be restricted to specific cell types. In the case of insulin or amylase secretion, both cAMP and calcium-mobilizing effects may be involved (25,26). VIP action has been associated with other second messengers in the central nervous system. Treatment of pinealocytes with low concentrations of VIP produced increases in intracellular calcium, concomitant with elevations in cGMP and a cyclic nucleotide-gated cation channel (27). Thus, mechanisms of VIP-mediated secretion and other functions are probably cell-specific.
Characterization of a novel stimulus-induced glial calcium wave in Drosophila larval peripheral segmental nerves and its role in PKG-modulated thermoprotection
Published in Journal of Neurogenetics, 2021
Jennifer L. Krill, Ken Dawson-Scully
The ER is responsible for maintaining low cytoplasmic levels of Ca2+. ATPases pump Ca2+ into the ER to accomplish this (Clapham, 2007; He, Lam, McCormick, & Distelhorst, 1997). In order to investigate the contribution, if any, of Ca2+ buffering by the ER in the observed peripheral glial Ca2+ wave, pharmacological agents were applied to the HL3 saline bath to inhibit either the uptake or release of Ca2+ by the ER. Thapsigargin is an inhibitor of the Ca2+-transporting ATPase that mediates the uptake of Ca2+ ions into the ER (Lytton, Westlin, & Hanley, 1991). The inhibition of ER Ca2+ uptake using Thapsigargin will also deplete Ca2+ stores within the ER as no additional Ca2+ can enter.
Extracellular esterase activity as an indicator of endoplasmic reticulum calcium depletion
Published in Biomarkers, 2018
Kathleen A. Trychta, Emily J. Heathward, Agnieszka Sulima, Susanne Bäck, Mehdi Farokhnia, Christopher T. Richie, Lorenzo Leggio, Kenner C. Rice, Brandon K. Harvey
Thapsigargin (Tg) pharmacologically depletes ER calcium by inhibiting the sarcoplasmic endoplasmic reticulum calcium ATPase (SERCA) (Davidson and Varhol, 1995). Our SH-SY5Y neuroblastoma cell line that stably expresses GLuc-ASARTDL has been previously characterized as a reporter of ER calcium depletion (Henderson et al. 2014). Here, we show that an increase in extracellular luminescence from GLuc-ASARTDL following Tg treatment was accompanied by an increase in fluorescence from esterase activity (Figure 3(a)). Tg did not cause any significant change in cell viability (Supplementary Figure 2(a,b)). Given that CES1 is a liver carboxylesterase and CES1 inhibitors decreased the esterase signal in previously tested samples, endogenous esterase activity was further tested in two human hepatoma cell lines, Hep3B and HepG2. Tg significantly increased media esterase activity in both cell lines (Figure 3(b)). BNPP and benzil (pan-carboxylesterase inhibitors), troglitazone (CES1 inhibitor), and loperamide (CES2 inhibitor) dose dependently reduced esterase activity indicating a carboxylesterase is responsible for the fluorescent signal being produced and that CES1 and CES2 can hydrolyze the ester bonds of fluorescein-CM2 (Figure 3(c)).
Targeting the integrated stress response in ophthalmology
Published in Current Eye Research, 2021
Hsiao-Sang Chu, Cornelia Peterson, Albert Jun, James Foster
Many toxins or drugs induce extensive ISR,103 including arsenic,104 tunicamycin,105 thapsigargin,106 and mitomycin C.107 Environmental arsenic contamination in drinking water has been a global health issue that was associated with many cancers.108 Arsenic generates oxidative stress and mediates ER and mitochondrial cross-talks that results in apoptosis via ATF4 regulated pathways.104 Arsenic-induced-VEGF production in retinal-pigmented epithelium via eIF2α-ATF4 branch has suggested non-hypoxic stresses also contributed to VEGF expression.98 Tunicamycin, an antibiotic mixture produced by Streptomyces lysosuperificus, has antimicrobial activity against bacteria, fungi, and viruses. Tunicamycin not only impairs protein glycosylation, but also depletes the calcium in ER which further aggravates unfolded proteins stress.105 Tunicamycin has not been used as human medicine103 due to its toxicity, but has been broadly applied as an ER stressor in studying various pathological and physiological processes of diabetes and asthma.109,110 Thapsigargin is a highly potent drug isolated from the plant Thapsia garganica L (Linnaeus),106 its cytotoxicity is derived from its ability to inhibit calcium transport leading to calcium depletion in ER. Therefore, in addition to ER stress-related cell death, thapsigargin induces concomitant increase in free cytosolic calcium is also a potent pro-apoptotic signal in cells.106 Mitomycin C, is a reactive oxygen species (ROS)-generating anticancer drug. Mitomycin C can induce human fibroblast apoptosis via PERK pathway,107 and its anti-fibrotic effect has been applied in many ophthalmic surgeries such as pterygium excision111 and glaucoma filtering surgery.112