scholarly journals The inhibition of the sarcoplasmic/endoplasmic reticulum Ca2+-ATPase by macrocyclic lactones and cyclosporin A

2002 ◽  
Vol 366 (1) ◽  
pp. 255-263 ◽  
Author(s):  
Jonathan G. BILMEN ◽  
Laura L. WOOTTON ◽  
Francesco MICHELANGELI
Keyword(s):  
Endoplasmic Reticulum ◽  
Cyclosporin A ◽  
Competitive Inhibition ◽  
Specific Inhibitor ◽  
Macrocyclic Lactones ◽  
Atpase Inhibitor ◽  
Fk 506 ◽  
Beneficial Effects ◽  
Parasitic Worm ◽  
High Concentrations

The pharmacology of macrocyclic lactones is varied, with many beneficial effects in treating disease processes. FK-506, rapamycin and ascomycin have been utilized as immunosuppressant agents. Ivermectin is typically used to treat parasitic worm infections in mammals. Another immunosuppressant, cyclosporin A, is a cyclic oligotide that has similar immunosuppressant properties to those exerted by macrocyclic lactones. Here we report on the inhibition by these compounds of sarcoplasmic/endoplasmic-reticulum Ca2+-ATPase (SERCA) Ca2+ pumps. Ivermectin, cyclosporin A and rapamycin all inhibited the skeletal muscle sarcoplasmic reticulum Ca2+-ATPase (SERCA1). In addition, although ivermectin inhibited brain microsomal endoplasmic reticulum (type 2b) Ca2+-ATPase, cyclosporin A and rapamycin did not. As cyclosporin A also did not inhibit cardiac Ca2+-ATPase activity, this would suggest that it could be an isoform-specific inhibitor. Ivermectin was shown to be the most potent Ca2+-ATPase inhibitor of the macrocyclic lactones (IC50 = 7μM). It appears to show a ‘competitive’ inhibition with respect to high concentrations of ATP by increasing the regulatory binding site Km but without affecting the catalytic site Km. In addition, ivermectin stabilizes the ATPase in an E1 conformational state, and inhibits Ca2+ release from the enzyme during turnover. This would suggest that ivermectin inhibits Ca2+ release from the luminal binding sites of the phosphoenzyme intermediate, a step that is known to be accelerated by high [ATP].

scholarly journals Acidocalcisomes in Toxoplasma gondii tachyzoites

1996 ◽  
Vol 313 (2) ◽  
pp. 655-659 ◽  
Author(s):  
Silvia N. J. MORENO ◽  
Li ZHONG
Keyword(s):  
Endoplasmic Reticulum ◽  
Toxoplasma Gondii ◽  
Mammalian Cells ◽  
Specific Inhibitor ◽  
Mitochondrial Atpase ◽  
Bafilomycin A1 ◽  
Atpase Inhibitor ◽  
Extracellular Medium ◽  
Acidic Compartment ◽  
Acidic Organelles

Toxoplasma gondii tachyzoites were loaded with the fluorescent indicator fura 2 to investigate the transport mechanisms involved in maintaining their intracellular Ca2+ homoeostasis. The mitochondrial ATPase inhibitor oligomycin and the endoplasmic-reticulum Ca2+-ATPase inhibitor thapsigargin increased the intracellular Ca2+ concentration ([Ca2+]i), thus indicating the requirement for ATP and the involvement of the endoplasmic reticulum in maintaining intracellular Ca2+ homoeostasis. The effect of thapsigargin was more accentuated in the presence of extracellular Ca2+, clearly showing that, as occurs with other eukaryotic cells, depletion of intracellular Ca2+ pools led to an increase in the uptake of Ca2+ from the extracellular medium. In addition to these results, we found evidence that, in contrast with what occurs in mammalian cells, T. gondii tachyzoites possess a significant amount of Ca2+ stored in an acidic compartment, termed the acidocalcisome, as indicated by: (1) the increase in [Ca2+]i induced by bafilomycin A1 (a specific inhibitor of H+-ATPases), nigericin (a K+/H+ exchanger) or the weak base NH4Cl, in the nominal absence of extracellular Ca2+ to preclude Ca2+ entry; and (2) the effect of ionomycin, a Ca2+-releasing ionophore that cannot take Ca2+ out of acidic organelles and that was more effective after alkalinization of these compartments by addition of bafilomycin A1, nigericin or NH4Cl. Considering the relative importance of the ionomycin-releasable and the ionomycin+NH4Cl-releasable Ca2+ pools, it is apparent that T. gondii tachyzoites contain a significant amount of Ca2+ stored in acidocalcisomes.

Metabolic effects of cyclosporin A and FK 506 in liver transplant recipients

Diabetes ◽  
1993 ◽  
Vol 42 (12) ◽  
pp. 1753-1759 ◽  
Author(s):  
A. J. Krentz ◽  
B. Dousset ◽  
D. Mayer ◽  
P. McMaster ◽  
J. Buckels ◽  
...  
Keyword(s):  
Liver Transplant ◽  
Cyclosporin A ◽  
Metabolic Effects ◽  
Transplant Recipients ◽  
Fk 506 ◽  
Liver Transplant Recipients

158Lipoprotein patterns in liver transplant patients: A comparison between cyclosporin A and FK 506

2000 ◽  
Vol 6 (3) ◽  
pp. C40-C40
Author(s):  
I GRAZIADEI ◽  
M LAIMER ◽  
K NACHBAUR ◽  
C EBENBICHLER ◽  
A KONIGSRAINER ◽  
...  
Keyword(s):  
Liver Transplant ◽  
Cyclosporin A ◽  
Fk 506 ◽  
Transplant Patients

Palmitate movement across red and white muscle membranes of rainbow trout

2004 ◽  
Vol 286 (1) ◽  
pp. R46-R53 ◽  
Author(s):  
Jeff G. Richards ◽  
Arend Bonen ◽  
George J. F. Heigenhauser ◽  
Chris M. Wood
Keyword(s):  
Fatty Acid ◽  
Rainbow Trout ◽  
White Muscle ◽  
Specific Inhibitor ◽  
Fatty Acid Binding ◽  
Rainbow Trout Oncorhynchus Mykiss ◽  
Fatty Acid Transporter ◽  
Palmitate Uptake ◽  
High Concentrations

We examined the movement of [3H]palmitate across giant sarcolemmal vesicles prepared from red and white muscle of rainbow trout ( Oncorhynchus mykiss). Red and white muscle fatty acid carriers have similar affinities for palmitate (apparent Km = 26 ± 6 and 33 ± 8 nM, respectively); however, red muscle has a higher maximal uptake compared with white muscle ( Vmax = 476 ± 41 vs. 229 ± 23 pmol·mg protein-1·s-1, respectively). Phloretin (250 μM) inhibited palmitate influx in red and white muscle vesicles by ∼40%, HgCl2 (2.5 mM) inhibited palmitate uptake by 20-30%, and the anion-exchange inhibitor DIDS (250 μM) inhibited palmitate influx in red and white muscle vesicles by ∼15 and 30%, respectively. Western blot analysis of red and white muscle vesicles did not detect a mammalian-type fatty acid transporter (FAT); however, preincubation of vesicles with sulfo- N-succinimidyloleate, a specific inhibitor of FAT in rats, reduced palmitate uptake in red and white muscle vesicles by ∼15 and 25%, respectively. A mammalian-type plasma membrane fatty acid-binding protein was identified in trout muscle using Western blotting, but the protein differed in size between red and white muscle. At low concentrations of free palmitate (2.5 nM), addition of high concentrations (111 μM total) of oleate (18:0) caused ∼50% reduction in palmitate uptake by red and white muscle vesicles, but high concentrations (100 μM) of octanoate (8:0) caused no inhibition of uptake. Five days of aerobic swimming at ∼2 body lengths/s and 9 days of chronic cortisol elevation in vivo, both of which stimulate lipid metabolism, had no effect on the rate of palmitate movement in red or white muscle vesicles.

The Mechanism of Action of FK-506 and Cyclosporin A

2006 ◽  
Vol 696 (1) ◽  
pp. 9-19 ◽  
Author(s):  
GREG WIEDERRECHT ◽  
ELSA LAM ◽  
SHIRLEY HUNG ◽  
MARY MARTIN ◽  
NOLAN SIGAL
Keyword(s):  
Cyclosporin A ◽  
Mechanism Of Action ◽  
Fk 506

Failure of FK-506, a new immunosuppressant, to prevent cerebral vasospasm in a canine two-hemorrhage model

1993 ◽  
Vol 79 (5) ◽  
pp. 710-715 ◽  
Author(s):  
Kazuya Nagata ◽  
Tomio Sasaki ◽  
Junichi Iwama ◽  
Takashi Mori ◽  
Shoko Iwamoto ◽  
...  
Keyword(s):  
Cyclosporin A ◽  
Cerebral Vasospasm ◽  
Basilar Artery ◽  
Interleukin 1 ◽  
Interleukin 2 ◽  
Muscle Layer ◽  
Treated Group ◽  
Control Group ◽  
Fk 506 ◽  
Content Type

✓ In order to clarify the possible role of immunological reaction in the pathogenesis of cerebral vasospasm, the authors examined the prophylactic effect of the immunosuppressant agents FK-506 and cyclosporin A on chronic vasospasm in a canine two-hemorrhage model. While a mean constriction of the basilar artery to 81.0% ± 4.0% (± standard error of the mean) occurred on Day 2 and to 63.8% ± 3.5% on Day 7 in the untreated group, constriction to 77.9% ± 3.4% on Day 2 and 62.8% ± 3.0% on Day 7 was demonstrated in the FK-506-treated group (difference not significant). This tendency was also noted in the cyclosporin A-treated group, with basilar artery constriction to 81.8% ± 3.7% and 56.3% ± 2.7%, respectively (difference not significant). The histological changes of the basilar artery, including corrugation of the elastic lamina, detachment of endothelial cells, and vacuolar formation in the smooth-muscle layer were not different in the two treated groups and the one control group. Since these immunosuppressant agents are known to inhibit the release of interleukin-2 (IL-2), the level of IL-2 was examined in the cerebrospinal fluid of patients with cerebral vasospasm. While interleukin-1 gradually increased in level as time passed, the level of IL-2 was consistently low during the course of the study, indicating less participation of IL-2 in the pathogenesis of cerebral vasospasm. This clinical observation matched the experimental results. The authors conclude that cell-mediated immunoreaction, initiated mainly by IL-2, plays little role in the pathogenesis of cerebral vasospasm.

Abstract 138: High Salt Intake Augments Excitability of Pre-sympathetic PVN Neurons Through Dysfunction of the Endoplasmic Reticulum Ca2+ ATPase

Hypertension ◽  
2015 ◽  
Vol 66 (suppl_1) ◽  
Author(s):  
Robert A Larson ◽  
Andrew D Chapp ◽  
Michael J Huber ◽  
Zixi Cheng ◽  
Zhiying Shan ◽  
...  
Keyword(s):  
Endoplasmic Reticulum ◽  
Salt Intake ◽  
Sympathetic Neurons ◽  
High Salt ◽  
Ventrolateral Medulla ◽  
Dependent Manner ◽  
Loss Of Function ◽  
Atpase Inhibitor ◽  
High Salt Intake ◽  
Significant Difference

High salt (HS) intake sensitizes pre-sympathetic neurons in the hypothalamic paraventricular nucleus (PVN) leading to augmented neuronal excitability. Recently, we reported that dysfunction of Ca 2+ dependent K + channels in the PVN contributes to HS intake induced sympathoexcitation. The endoplasmic reticulum (ER) acts as a Ca 2+ store and plays an important role in regulating intracellular Ca 2+ homeostasis. The ER Ca 2+ ATPase is responsible for maintaining the high level of ER Ca 2+ and loss of function would deplete the Ca 2+ store contributing to the reduced activity of Ca 2+ dependent K + channels. We hypothesized that a 2% (NaCl) HS diet for 5 weeks would reduce function of the ER Ca 2+ ATPase and augment excitability of PVN neurons with axon projections to the rostral ventrolateral medulla (PVN-RVLM) identified by retrograde label. In whole cell current-clamp recordings from PVN-RVLM neurons, graded current injections evoked graded increases in spike frequency. Maximum discharge was evoked by +200 pA injections and averaged 22±2 Hz (n=6) in normal salt (NS) control and was significantly augmented (p<0.05) by HS diet 34±5 Hz (n=8). Bath application of thapsigargin (TG) (0.5 μM), the ER Ca 2+ ATPase inhibitor, augmented excitability of PVN-RVLM neurons in NS (32±4 Hz, n=5, p<0.05), yet had no significant effect in HS rats (32±6 Hz, n=6). ER Ca 2+ ATPase function was assessed in whole animal preparations by bilateral PVN microinjection of TG in anesthetized rats. PVN microinjection of TG (0.15, 0.3 0.75 and 1.5 nmol/100nl) increased sympathetic nerve activity (SNA) and mean arterial pressure (MAP) in a dose-dependent manner in NS rats. Maximum increases in splanchnic SNA (SSNA), renal SNA (RSNA) and MAP elicited by PVN TG (0.75 nmol/100nl; n=5) were 93±7%, 75±7%, and 11±2mmHg, respectively. In contrast, sympathoexcitatory responses to PVN TG (0.75 nmol/100nl; n=5) were attenuated in HS treated rats (SSNA 41±8%, RSNA 22±5%, p<0.05 vs. NS) while MAP responses demonstrated no significant difference (+8±2 mmHg, p>0.05 vs NS). Our data indicate that a HS diet reduces ER Ca 2+ ATPase activity and augments excitability of PVN-RVLM neurons in vitro. Altered ER Ca 2+ homeostasis may contribute to sympathoexcitation through loss of Ca 2+ dependent K + channel activity in the PVN.

Chemoattractants: Their essentiality and efficacy in shrimp aquaculture

2021 ◽  
Vol 68 (1) ◽  
Author(s):  
R. Jannathulla ◽  
O. Sravanthi ◽  
H. Imran Khan ◽  
H. Syed Moomeen ◽  
A. Gomathi ◽  
...  
Keyword(s):  
Chemical Compounds ◽  
Nutritional Composition ◽  
Present Review ◽  
Shrimp Aquaculture ◽  
Aquatic Species ◽  
Beneficial Effects ◽  
Shrimp Feed ◽  
High Concentrations ◽  
Plant Sources ◽  
Selection Of

Aquaculture serves as a sustainable source of good quality wholesome food and major input is feed. In recent years, considerable quantities of plant sources have been attempted for inclusion in shrimp feed, due to high demand and high cost of fishmeal. Plant-based ingredients are in general poor in attractability and palatability to aquatic species compared to marine sources. It is desirable to develop an economical and nutritious feed that is attractive and palatable for ensuring reduction of feed wastage. Chemoattractants nowadays are unavoidable in commercial shrimp feeds and are included either individually or in combination. The present review revealed that the various marine sources, in particular krill meal would be more effective for aquatic species, compared to those derived from vegetable origin and chemical compounds. In addition to acting as a feed attractant, marine sources serve as a potential fishmeal substitute due to their rich nutritional composition. However, certain biogenic amines present in these marine-based ingredients need to be examined before their use, since these amines when present in high concentrations reduces feed intake by producing undesirable odour. Use of a combination of chemoattractants would give a better effect, rather than using them individually and compounds from plant origin have limited beneficial effects. The present review concludes that incorporation of chemoattractants would be beneficial in formulation of enriched and economical feeds with better attractability and palatability. The selection of suitable attractant and their supplementation at correct proportion is significantly more important to avoid undesirable effects in cultured shrimp. Further field-based research is needed to predict the actual effects of chemoattractants on farmed shrimp and to provide a sustainable base for the expansion of shrimp aquaculture sector, by reducing feed wastage.

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