Mechanism of Inhibition of the Ca2+-ATPase by Spermine and Other Polycationic Compounds

Hughes, Graham M.; Ap, Starling; Jm, East; Ag, Lee

doi:10.1021/bi00182a001

Cited by 21 publications

(29 citation statements)

References 60 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Further, processing of A␤ (13) and other proteins (14,15) involved in neurodegenerative diseases seems to be associated with cholesterol-enriched membrane microdomains (lipid rafts) that can be isolated from neuronal plasma membranes (16) and other membranes based on their resistance to solubilization in nonionic detergents. Although the full-length A␤ contains 39 to 43 amino acid residues, it has been shown that the amyloid ␤-fragment 25-35 (A␤25- 35) represents the biologically active region of the full peptide and exhibits the same neurotoxic effect as the full-length peptide (17). Here, we relate changes in Ca 2ϩ -ATPase function in human brain affected by AD to effects of A␤ on the three types of Ca 2ϩ -ATPases.…”

mentioning

confidence: 96%

Altered Ca ²⁺ dependence of synaptosomal plasma membrane Ca ²⁺ ‐ATPase in human brain affected by Alzheimer's disease

Berrocal¹,

Marcos²,

Sepúlveda³

et al. 2009

FASEB j.

View full text Add to dashboard Cite

High-affinity Ca(2+) transport ATPases play a crucial role in controlling cytosolic Ca(2+). The amyloid beta-peptide (Abeta) is a neurotoxic agent found in affected neurons in Alzheimer's disease (AD) that has been implicated in dysregulation of Ca(2+) homeostasis. Using kinetic assays, we have shown that the Ca(2+) dependencies of intracellular Ca(2+)-ATPase (SERCA and SPCA) activity are the same in human AD and normal brain but that of plasma membrane Ca(2+)-ATPase (PMCA) is different. The addition of Abeta to normal brain decreases the PMCA activity measured at pCa 5.5, resulting in the same Ca(2+)dependency as that seen in AD brain, whereas the addition of Abeta to AD brain has no effect on PMCA activity. Abeta also decreases the activity of PMCA purified from pig cerebrum, the effect being isoform specific. The level of inhibition of purified PMCA caused by Abeta is reduced by cholesterol, and the level of inhibition of PMCA activity by Abeta in the raft fraction of pig synaptosomal membranes is lower than for the nonraft fraction. We conclude that the effect of Abeta on PMCA activity could be important in amyloid toxicity, resulting in cytoplasmic Ca(2+) dysregulation and could explain the different Ca(2+) dependencies of PMCA activity observed in normal and AD brain.

show abstract

mentioning

confidence: 96%

Altered Ca ²⁺ dependence of synaptosomal plasma membrane Ca ²⁺ ‐ATPase in human brain affected by Alzheimer's disease

Berrocal¹,

Marcos²,

Sepúlveda³

et al. 2009

FASEB j.

View full text Add to dashboard Cite

show abstract

“…Thapsivillosin A also binds to the ATPase with high affinity, to give a modified E2 state of the ATPase [26]. In the presence of Ca# + and ATP at pH 6.0, the ATPase was maximally phosphorylated (Table 1 ; [29]) ; labelling the ATPase with DMC had no effect on 4 2 − can bind to the ATPase, but only H 2 PO 4 − can phosphorylate it. Curve c also includes the effects of pH and Mg 2 + on the E1-E2 equilibrium for the ATPase, calculated using the parameters given in Lee et al [31].…”

Section: Resultsmentioning

confidence: 99%

Effects of pH on phosphorylation of the Ca2+-ATPase of sarcoplasmic reticulum by inorganic phosphate

Khan

East

Lee

1997

Biochemical Journal

View full text Add to dashboard Cite

The fluorescence intensity of the Ca# + -ATPase of skeletal muscle sarcoplasmic reticulum (SR) labelled with 4-(bromomethyl)-6,7-dimethoxycoumarin has been shown to decrease on phosphorylation of the ATPase with P i , this providing a convenient measure of the level of phosphorylation. Comparison of the fluorescence decrease observed with ATP and with high concentrations of P i fix the value of the equilibrium constant for the phosphorylation reaction E2PMg 8 E2P i Mg at pH 6.0 at about 2. Studies of the pH-dependence of phosphorylation show

show abstract

“…Additionally, other as yet unidentified proteins have been noted to exhibit the ability to effect phospholipid transbilayer movement (55,56). Thus which candidate flippase is active in HL-60s undergoing apoptosis and whether it, or modulators of its activity (60,61), interacts with polyamines is the goal of future studies. We note that several proteins, protein kinase CK2 (46,62) and the inward rectifier potassium channel (38,63,64), have binding sites for spermine and are specifically regulated by it, thus setting precedence for polyamine regulation of protein function.…”

Section: Discussionmentioning

confidence: 99%

Polyamine Regulation of Plasma Membrane Phospholipid Flip-Flop during Apoptosis

Bratton

Fadok

Richter

et al. 1999

Journal of Biological Chemistry

View full text Add to dashboard Cite

During apoptosis, phosphatidylserine (PS) is moved from the plasma membrane inner leaflet to the outer leaflet where it triggers recognition and phagocytosis of the apoptotic cell. Although the mechanisms of PS appearance during apoptosis are not well understood, it is thought that declining activity of the aminophospholipid translocase and calcium-mediated, nonspecific flip-flop of phospholipids play a role. As previous studies in the erythrocyte ghost have shown that polyamines can alter flip-flop of phospholipids, we asked whether alterations in cellular polyamines in intact cells undergoing apoptosis would affect PS appearance, either by altering aminophospholipid translocase activity or phospholipid flip-flop. Cells of the human leukemic cell line, HL-60, were incubated with or without the ornithine decarboxylase inhibitor, difluoromethylornithine (DFMO), and induced to undergo apoptosis by ultraviolet irradiation. Whereas DFMO treatment resulted in profound depletion of putrescine and spermidine (but not spermine), it had no effect on caspase activity, DNA fragmentation, or plasma membrane vesiculation, typical characteristics of apoptosis. Notably, DFMO treatment prior to ultraviolet irradiation did not alter the decline in PS inward movement by the aminophospholipid translocase as measured by the uptake of 6-[(7-nitrobenz-2-oxa-1,3-diazol-4-yl)aminocaproyl] (NBD)-labeled PS detected in the flow cytometer. Conversely, the appearance of endogenous PS in the plasma membrane outer leaflet detected with fluorescein isothiocyanatelabeled annexin V and enhanced phospholipid flip-flop detected by the uptake of 1-palmitoyl-1-[6-[(7-nitro-2-1,3-benzoxadiazol-4-yl)aminocaproyl]-sn-glycero-3-phosphocholine (NBD-PC) seen during apoptosis were significantly inhibited by prior DFMO treatment. Importantly, replenishment of spermidine, by treatment with exogenous putrescine to bypass the metabolic blockade by DFMO, restored both enhanced phospholipid flip-flop and appearance of PS during apoptosis. Such restoration was seen even in the presence of cycloheximide but was not seen when polyamines were added externally just prior to assay. Taken together, these data show that intracellular polyamines can modulate PS appearance resulting from nonspecific flip-flop of phospholipids across the plasma membrane during apoptosis.Under normal conditions, plasma membrane phospholipids of cells appear to be asymmetrically distributed across the bilayer with phosphatidylserine found almost entirely in the inner leaflet and sphingomyelin in the outer leaflet of the bilayer (1-3) . Maintenance of this asymmetry is attributed largely to the activity of the aminophospholipid translocase that moves phosphatidylserine (PS) 1 and, with a lesser affinity, phosphatidylethanolamine from the outer to the inner leaflet (4 -7). On the other hand, the appearance of PS, seen as a universal feature of apoptosis (3,8,9), and phospholipid flipflop during inflammatory cell activation (10 -13) require enhanced, nonspecific (with regard to head group) tra...

show abstract

Mechanism of Inhibition of the Ca2+-ATPase by Spermine and Other Polycationic Compounds

Cited by 21 publications

References 60 publications

Altered Ca ²⁺ dependence of synaptosomal plasma membrane Ca ²⁺ ‐ATPase in human brain affected by Alzheimer's disease

Altered Ca ²⁺ dependence of synaptosomal plasma membrane Ca ²⁺ ‐ATPase in human brain affected by Alzheimer's disease

Effects of pH on phosphorylation of the Ca2+-ATPase of sarcoplasmic reticulum by inorganic phosphate

Polyamine Regulation of Plasma Membrane Phospholipid Flip-Flop during Apoptosis

Contact Info

Product

Resources

About

Mechanism of Inhibition of the Ca2+-ATPase by Spermine and Other Polycationic Compounds

Cited by 21 publications

References 60 publications

Altered Ca 2+ dependence of synaptosomal plasma membrane Ca 2+ ‐ATPase in human brain affected by Alzheimer's disease

Altered Ca 2+ dependence of synaptosomal plasma membrane Ca 2+ ‐ATPase in human brain affected by Alzheimer's disease

Effects of pH on phosphorylation of the Ca2+-ATPase of sarcoplasmic reticulum by inorganic phosphate

Polyamine Regulation of Plasma Membrane Phospholipid Flip-Flop during Apoptosis

Contact Info

Product

Resources

About

Altered Ca ²⁺ dependence of synaptosomal plasma membrane Ca ²⁺ ‐ATPase in human brain affected by Alzheimer's disease

Altered Ca ²⁺ dependence of synaptosomal plasma membrane Ca ²⁺ ‐ATPase in human brain affected by Alzheimer's disease