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1.

Background

TIM15/Zim17 in yeast and its mammalian ortholog Hep are Zn2 + finger (Cys4) proteins that assist mtHsp70 in protein import into the mitochondrial matrix.

Methods

Here we characterized the Zn2 + induced TIM15 folding integrating biophysical and computational approaches.

Results

TIM15 folding occurs from an essentially unstructured conformation to a Zn2 +-coordinated protein in a fast and markedly temperature-dependent process. Moreover, we demonstrate unambiguously that Zn2 + induced TIM15 folding is essential for its role as mtHsp70 chaperone since in the unstructured apo state TIM15 does not bind to mtHsp70 and is unable to prevent its aggregation. Molecular dynamics simulations help to understand the crucial role of Zn2 + in promoting a stable and functional 3D architecture in TIM15. It is shown that the metal ion, through its coordinating cysteine residues, can mediate relevant long-range effects with the interaction interface for mtHsp70 coupling thus folding and function.

Conclusions

Zn2 + induced TIM15 folding is essential for its function and likely occurs in mitochondrial matrix where high concentrations of Zn2 + were reported.

General significance

The combination of experimental and computational approaches presented here provide an integrated structural, kinetic and thermodynamic view of the folding of a mitochondrial zinc finger protein, which might be relevant to understand the organelle import of proteins sharing this fold.  相似文献   

2.

Background

Serum albumin is the major protein component of blood plasma and is responsible for the circulatory transport of a range of small molecules that include fatty acids, hormones, metal ions and drugs. Studies examining the ligand-binding properties of albumin make up a large proportion of the literature. However, many of these studies do not address the fact that albumin carries multiple ligands (including metal ions) simultaneously in vivo. Thus the binding of a particular ligand may influence both the affinity and dynamics of albumin interactions with another.

Scope of review

Here we review the Zn2 + and fatty acid transport properties of albumin and highlight an important interplay that exists between them. Also the impact of this dynamic interaction upon the distribution of plasma Zn2 +, its effect upon cellular Zn2 + uptake and its importance in the diagnosis of myocardial ischemia are considered.

Major conclusions

We previously identified the major binding site for Zn2 + on albumin. Furthermore, we revealed that Zn2 +-binding at this site and fatty acid-binding at the FA2 site are interdependent. This suggests that the binding of fatty acids to albumin may serve as an allosteric switch to modulate Zn2 +-binding to albumin in blood plasma.

General significance

Fatty acid levels in the blood are dynamic and chronic elevation of plasma fatty acid levels is associated with some metabolic disorders such as cardiovascular disease and diabetes. Since the binding of Zn2 + to albumin is important for the control of circulatory/cellular Zn2 + dynamics, this relationship is likely to have important physiological and pathological implications. This article is part of a Special Issue entitled Serum Albumin.  相似文献   

3.

Background

Serum albumin is the most abundant protein in the blood and cerebrospinal fluid and plays a fundamental role in the distribution of essential transition metal ions in the human body. Human serum albumin (HSA) is an important physiological transporter of the essential metal ions Cu2 +, and Zn2 + in the bloodstream. Its binding of metals like Ni2 +, Co2 +, or Cd2 + can occur in vivo, but is only of toxicological relevance. Moreover, HSA is one of the main targets and hence most studied binding protein for metallodrugs based on complexes with Au, Pt and V.

Scope of Review

We discuss i) the four metal-binding sites so far described on HSA, their localization and metal preference, ii) the binding of the metal ions mentioned above, i.e. their stability constants and association/dissociation rates, their coordination chemistry and their selectivity versus the four binding sites iii) the methodology applied to study issues of items i and ii and iv) oligopeptide models of the N-terminal binding site.

Major Conclusions

Albumin has four partially selective metal binding sites with well-defined metal preferences. It is an important regulator of the blood transport of physiological Cu(II) and Zn(II) and toxic Ni(II) and Cd(II). It is also an important target for metal-based drugs containing Pt(II), V(IV)O, and Au(I).

General Significance

The thorough understanding of metal binding properties of serum albumin, including the competition of various metal ions for specific binding sites is important for biomedical issues, such as new disease markers and design of metal-based drugs. This article is part of a Special Issue entitled Serum Albumin.  相似文献   

4.

Background

Dietary and recycled iron are in the Fe2 + oxidation state. However, the metal is transported in serum by transferrin as Fe3 +. The multi-copper ferroxidase ceruloplasmin is suspected to be the missing link between acquired Fe2 + and transported Fe3 +.

Methods

This study uses the techniques of chemical relaxation and spectrophotometric detection.

Results

Under anaerobic conditions, ceruloplasmin captures and oxidizes two Fe2 +. The first uptake occurs in domain 6 (< 1 ms) at the divalent iron-binding site. It is accompanied by Fe2 + oxidation by Cu2 +D6. Fe3 + is then transferred from the binding site to the holding site. Cu+D6 is then re-oxidized by a Cu2 + of the trinuclear cluster in about 200 ms. The second Fe2 + uptake and oxidation involve domain 4 and are under the kinetic control of a 200 s change in the protein conformation. With transferrin and in the formed ceruloplasmin–transferrin adduct, two Fe3 + are transferred from their holding sites to two C-lobes of two transferrins. The first transfer (~ 100 s) is followed by conformation changes (500 s) leading to the release of monoferric transferrin. The second transfer occurs in two steps in the 1000–10,000 second range.

Conclusion

Fe3 + is transferred after Fe2 + uptake and oxidation by ceruloplasmin to the C-lobe of transferrin in a protein–protein adduct. This adduct is in a permanent state of equilibrium with all the metal-free or bounded ceruloplasmin and transferrin species present in the medium.

General significance

Ceruloplasmin is a go-between dietary or recycled Fe2 + and transferrin transported Fe3 +.  相似文献   

5.

Background

Tryptophan-histidine (Trp-His) was found to suppress the activity of the Ca2 +/calmodulin (CaM)-dependent protein kinases II (CaMKII), which requires the Ca2 +-CaM complex for an initial activation. In this study, we attempted to clarify whether Trp-His inhibits Ca2 +-CaM complex formation, a CaMKII activator.

Methods

The ability of Trp-His and other peptides to inhibit Ca2 +-CaM complex formation was investigated by a Ca2 +-encapsulation fluorescence assay. The peptide-CaM interactions were illustrated by molecular dynamic simulation.

Results

We showed that Trp-His inhibited Ca2 +-CaM complex formation with a 1:1 binding stoichiometry of the peptide to CaM, considering that Trp-His reduced Hill coefficient of Ca2 +-CaM binding from 2.81 to 1.92. His-Trp also showed inhibitory activity, whereas Trp + His, 3-methyl His-Trp, and Phe-His did not show significant inhibitory activity, suggesting that the inhibitory activity was due to a peptide skeleton (irrespective of the sequence), a basic amino acid, a His residue, the N hydrogen atom of its imidazole ring, and Trp residue. In silico studies suggested the possibility that Trp-His and His-Trp interacted with the Ca2 +-binding site of CaM by forming hydrogen bonds with key Ca2 +-binding residues of CaM, with a binding free energy of − 49.1 and − 68.0 kJ/mol, respectively.

Conclusions

This is the first study demonstrating that the vasoactive dipeptide Trp-His possesses inhibitory activity against Ca2 +-CaM complex formation, which may elucidate how Trp-His inhibited CaMKII in a previous study.

General significance

The results provide a basic idea that could lead to the development of small peptides binding with high affinity to CaM and inhibiting Ca2 +-CaM complex formation in the future.  相似文献   

6.

Aim

Promoter-targeted small activating RNAs (saRNAs) have been shown to be able to induce target gene expression, a mechanism known as RNA activation (RNAa). The present study tested whether saRNA can induce the overexpression of TRPV5 in human cells derived from the kidney and subsequently manipulate cell calcium uptake.

Main methods

Three saRNAs complementary to the TRPV5 promoter were synthesized and transfected into cells. TRPV5 expression at the RNA and protein levels was analyzed by quantitative real-time PCR and Western blotting respectively. For functional study, transcellular Ca2 + transportation was tested by fura-2 analysis. Dihydrotestosterone (DHT), a suppressor of cellular calcium transportation, was administered to challenge the activating effect of selected saRNA.

Key findings

One of these synthesized saRNAs, ds-2939, significantly induced the expression of TRPV5 at both mRNA and protein levels. Fura-2 analysis revealed that the intracellular Ca2 + concentration was elevated by ds-2939. DHT treatment reduced transmembrane Ca2 + transport, which was partially antagonized by ds-2939.

Significance

Our results suggest that a saRNA targeting TRPV5 promoter can be utilized to manipulate the transmembrane Ca2 + transport by upregulating the expression of TRPV5 and may serve as an alternative for the treatment of Ca2 + balance-related diseases.  相似文献   

7.

Background

Acute renal failure is a serious complication of human envenoming by Bothrops snakes. The ion pump Na+/K+-ATPase has an important role in renal tubule function, where it modulates sodium reabsorption and homeostasis of the extracellular compartment. Here, we investigated the morphological and functional renal alterations and changes in Na+/K+-ATPase expression and activity in rats injected with Bothrops alternatus snake venom.

Methods

Male Wistar rats were injected with venom (0.8 mg/kg, i.v.) and renal function was assessed 6, 24, 48 and 72 h and 7 days post-venom. The rats were then killed and renal Na+/K+-ATPase activity was assayed based on phosphate release from ATP; gene and protein expressions were assessed by real time PCR and immunofluorescence microscopy, respectively.

Results

Venom caused lobulation of the capillary tufts, dilation of Bowman's capsular space, F-actin disruption in Bowman's capsule and renal tubule brush border, and deposition of collagen around glomeruli and proximal tubules that persisted seven days after envenoming. Enhanced sodium and potassium excretion, reduced proximal sodium reabsorption, and proteinuria were observed 6 h post-venom, followed by a transient decrease in the glomerular filtration rate. Gene and protein expressions of the Na+/K+-ATPase α1 subunit were increased 6 h post-venom, whereas Na+/K+-ATPase activity increased 6 h and 24 h post-venom.

Conclusions

Bothrops alternatus venom caused marked morphological and functional renal alterations with enhanced Na+/K+-ATPase expression and activity in the early phase of renal damage.

General significance

Enhanced Na+/K+-ATPase activity in the early hours after envenoming may attenuate the renal dysfunction associated with venom-induced damage.  相似文献   

8.

Background

The effect of indomethacin (INDO) on Ca2 + mobilization, cytotoxicity, apoptosis and caspase activation and the potential protective effect of quercetin (QUE), resveratrol (RES) and rutin (RUT) were determined in Caco-2 cells.

Methods

Caco-2 cells were incubated with INDO in the presence or absence of QUE, RES or RUT. The concentrations of Ca2 + in the cytosol (Fluo-3 AM) and mitochondria (Rhod-2 AM) were determined as well as the cytotoxicity (MTT reduction and LDH leakage), apoptosis (TUNEL) and caspase-3 and 9 activities.

Results

INDO promoted Ca2 + efflux from the endoplasmic reticulum (ER), resulting in an early, but transient, increment of cytosolic Ca2 + at 3.5 min, followed by a subsequent increment of intra-mitochondrial Ca2 + at 24 min. INDO also induced cytotoxicity, apoptosis, and increased caspase activities and cytochrome c release. All these alterations were prevented by the inhibitors of the IP3R and RyR receptors, 2-Aminoethoxydiphenyl borate (2-APB) and dantrolene. QUE was the most efficient polyphenol in preventing Ca2 + mobilization induced by INDO and all of its consequences including cytotoxicity and apoptosis.

Conclusions

In Caco-2 cells, INDO stimulates ER Ca2 + mobilization, probably through the activation of IP3R and RyR receptors, and the subsequent entry of Ca2 + into the mitochondria. Polyphenols protected the cells against the Ca2 + mobilization induced by INDO and its consequences on cytotoxicity and apoptosis.

General significance

These results confirm the possibility of using polyphenols and particularly QUE for the protection of the gastroduodenal mucosa in subjects consuming NSAIDs.  相似文献   

9.

Background

In recent years, as our understanding of the various roles played by Ca2 + signaling in development and differentiation has expanded, the challenge of imaging Ca2 + dynamics within living cells, tissues, and whole animal systems has been extended to include specific signaling activity in organelles and non-membrane bound sub-cellular domains.

Scope of review

In this review we outline how recent advances in genetics and molecular biology have contributed to improving and developing current bioluminescence-based Ca2 + imaging techniques. Reporters can now be targeted to specific cell types, or indeed organelles or domains within a particular cell.

Major conclusions

These advances have contributed to our current understanding of the specificity and heterogeneity of developmental Ca2 + signaling. The improvement in the spatial resolution that results from specifically targeting a Ca2 + reporter has helped to reveal how a ubiquitous signaling messenger like Ca2 + can regulate coincidental but different signaling events within an individual cell; a Ca2 + signaling paradox that until now has been hard to explain.

General significance

Techniques used to target specific reporters via genetic means will have applications beyond those of the Ca2 + signaling field, and these will, therefore, make a significant contribution in extending our understanding of the signaling networks that regulate animal development. This article is part of a Special Issue entitled Biochemical, biophysical and genetic approaches to intracellular calcium signalling.  相似文献   

10.

Background

Sleep is a physiological event that directly influences health by affecting the immune system, in which calcium (Ca2 +) plays a critical signaling role. We performed live cell measurements of cytosolic Ca2 + mobilization to understand the changes in Ca2 + signaling that occur in splenic immune cells after various periods of sleep deprivation (SD).

Methods

Adult male mice were subjected to sleep deprivation by platform technique for different periods (from 12 to 72 h) and Ca2 + intracellular fluctuations were evaluated in splenocytes by confocal microscopy. We also performed spleen cell evaluation by flow cytometry and analyzed intracellular Ca2 + mobilization in endoplasmic reticulum and mitochondria. Additionally, Ca2 + channel gene expression was evaluated

Results

Splenocytes showed a progressive loss of intracellular Ca2 + maintenance from endoplasmic reticulum (ER) stores. Transient Ca2 + buffering by the mitochondria was further compromised. These findings were confirmed by changes in mitochondrial integrity and in the performance of the store operated calcium entry (SOCE) and stromal interaction molecule 1 (STIM1) Ca2 + channels.

Conclusions and general significance

These novel data suggest that SD impairs Ca2 + signaling, most likely as a result of ER stress, leading to an insufficient Ca2 + supply for signaling events. Our results support the previously described immunosuppressive effects of sleep loss and provide additional information on the cellular and molecular mechanisms involved in sleep function.  相似文献   

11.

Aims

This experiment investigated the effects of sub-chronic aluminum chloride (AlCl3) exposure on rat ovaries.

Main methods

Eighty female Wistar (5 weeks old) rats, weighed 110–120 g, were randomly divided into four treatment groups: control group (CG), low-dose group (LG, 64 mg/kg BW AlCl3), mid-dose group (MG, 128 mg/kg BW AlCl3) and high-dose group (HG, 256 mg/kg BW AlCl3). The AlCl3 was administered in drinking water for 120 days. The ovarian ultrastructure was observed. The activities of acid phosphatase (ACP), alkaline phosphatase (ALP), succinate dehydrogenase (SDH), Na+–K+-ATPase, Mg2 +-ATPase and Ca2 +-ATPase, the contents of Fe, Cu and Zn, and the protein expression of follicle-stimulating hormone receptor (FSHR) and luteinizing hormone receptor (LHR) in the ovary were determined.

Key findings

The results showed that the structure of the ovary was disrupted, the activities of ALP, ACP, SDH, Na+–K+-ATPase, Mg2 +-ATPase and Ca2 +-ATPase, the contents of Zn, Fe and the protein expression of FSHR and LHR were lowered, and the content of Cu was increased in AlCl3-treated rats than those in control.

Significance

The results indicate that sub-chronic AlCl3 exposure caused the damage of the ovarian structure, the disturbed metabolism of Fe, Zn and Cu and the decreased activities of Na+–K+-ATPase, Mg2 +-ATPase and Ca2 +-ATPase in the ovary, which could result in suppressed energy supply in the ovary. A combination of suppression of energy supply and reduction of expression of FSHR and LHR could inhibit ovulation and corpus luteum development, leading to infertility in female rats.  相似文献   

12.

Background

Ca2 + is a ubiquitous and versatile second messenger that transmits information through changes of the cytosolic Ca2 + concentration. Recent investigations changed basic ideas on the dynamic character of Ca2 + signals and challenge traditional ideas on information transmission.

Scope of review

We present recent findings on key characteristics of the cytosolic Ca2 + dynamics and theoretical concepts that explain the wide range of experimentally observed Ca2 + signals. Further, we relate properties of the dynamical regulation of the cytosolic Ca2 + concentration to ideas about information transmission by stochastic signals.

Major conclusions

We demonstrate the importance of the hierarchal arrangement of Ca2 + release sites on the emergence of cellular Ca2 + spikes. Stochastic Ca2 + signals are functionally robust and adaptive to changing environmental conditions. Fluctuations of interspike intervals (ISIs) and the moment relation derived from ISI distributions contain information on the channel cluster open probability and on pathway properties.

General significance

Robust and reliable signal transduction pathways that entail Ca2 + dynamics are essential for eukaryotic organisms. Moreover, we expect that the design of a stochastic mechanism which provides robustness and adaptivity will be found also in other biological systems. Ca2 + dynamics demonstrate that the fluctuations of cellular signals contain information on molecular behavior. This article is part of a Special Issue entitled Biochemical, biophysical and genetic approaches to intracellular calcium signaling.  相似文献   

13.

Background

DNase antibodies can play an important role in the pathogenesis of different autoimmune pathologies.

Methods

An immunoglobulin light chain phagemid library derived from peripheral blood lymphocytes of patients with systemic lupus erythematosus (SLE) was used. The small pools of phage particles displaying DNA binding light chains with different for DNA were isolated by affinity chromatography on DNA-cellulose and the fraction eluted with 0.5 M NaCl was used for preparation of individual monoclonal light chains (MLChs, 28 kDa). Forty-five of 451 individual colonies were randomly chosen for a study of MLChs with DNase activity. The clones were expressed in Escherichia coli in a soluble form, and MLChs were purified by metal chelating chromatography followed by gel filtration, and studied in detail.

Results

Fifteen of 45 MLChs efficiently hydrolyzed DNA, and fourteen of them demonstrated various optimal concentrations of KCl or NaCl in a 1–100 mM range and showed one or two pH optima in a 4.8–9.1 range. All MLChs were dependent on divalent metal cations: the ratio of relative DNase activity in the presence of Mn2 +, Ca2 +, Mg2 +, Ni2 +, Zn2 +, Cu2 +, and Co2 + was individual for each MLCh preparation. Fourteen MLChs demonstrated a comparable affinity for DNA (260–320 nM), but different kcat values (0.02–0.7 min− 1).

Conclusions

These observations suggest an extreme diversity of DNase abzymes from SLE patients.

General significance

SLE light chain repertoire can serve as a source of new types of DNases.  相似文献   

14.

Background

Calcium (Ca2 +) oscillations are ubiquitous signals present in all cells that provide efficient means to transmit intracellular biological information. Either spontaneously or upon receptor ligand binding, the otherwise stable cytosolic Ca2 + concentration starts to oscillate. The resulting specific oscillatory pattern is interpreted by intracellular downstream effectors that subsequently activate different cellular processes. This signal transduction can occur through frequency modulation (FM) or amplitude modulation (AM), much similar to a radio signal. The decoding of the oscillatory signal is typically performed by enzymes with multiple Ca2 + binding residues that diversely can regulate its total phosphorylation, thereby activating cellular program. To date, NFAT, NF-κB, CaMKII, MAPK and calpain have been reported to have frequency decoding properties.

Scope of review

The basic principles and recent discoveries reporting frequency decoding of FM Ca2 + oscillations are reviewed here.

Major conclusions

A limited number of cellular frequency decoding molecules of Ca2 + oscillations have yet been reported. Interestingly, their responsiveness to Ca2 + oscillatory frequencies shows little overlap, suggesting their specific roles in cells.

General significance

Frequency modulation of Ca2 + oscillations provides an efficient means to differentiate biological responses in the cell, both in health and in disease. Thus, it is crucial to identify and characterize all cellular frequency decoding molecules to understand how cells control important cell programs.  相似文献   

15.
16.

Aim

The aim of this study was to identify the effects of swimming training on the mRNA expression and protein levels of the calcium handling proteins in the hearts of renovascular hypertensive rats submitted to swimming protocol during 6 weeks.

Main methods

Fischer rats with renovascular hypertension 2-kidney 1-clip (2K1C) and SHAM groups were divided among sedentary and exercised groups. The exercise protocol lasted for 6 weeks (1 h/day, 5×/week), and the mean arterial pressure, cardiomyocytes hypertrophy parameters, mRNA expression and protein levels of some calcium handling proteins in the left ventricle were evaluated.

Key findings

Swimming training was able to reduce the levels of mean arterial pressure in the hypertensive group compared to 2K1C SED, and to promote cardiac hypertrophy in SHAM EX and 2K1C EX groups in comparison to the respective control groups. The mRNA levels of B-type natriuretic peptide were reduced in the 2K1C EX when compared to 2K1C SED. The mRNA and protein levels of the sarcoplasmic reticulum Ca2 +-ATPase increased after the swimming training in SHAM and 2K1C groups. The mRNA and protein levels of phospholamban, displayed an increase in their levels in the exercised SHAM and in hypertensive rats in comparison to their respective controls; while mRNA levels of Na+/Ca2 + exchanger was reduced in the left ventricle comparing to the sedentary hypertensive rats.

Significance

Taken altogether, we provide evidence that the aerobic training may lead to cardiac remodeling, and modulate the calcium handling proteins expression in the heart of hypertensive rats.  相似文献   

17.

Aims/hypothesis

Changes in cellular cholesterol level may contribute to beta cell dysfunction. Islets from low density lipoprotein receptor knockout (LDLR−/−) mice have higher cholesterol content and secrete less insulin than wild-type (WT) mice. Here, we investigated the association between cholesterol content, insulin secretion and Ca2 + handling in these islets.

Methods

Isolated islets from both LDLR−/− and WT mice were used for measurements of insulin secretion (radioimmunoassay), cholesterol content (fluorimetric assay), cytosolic Ca2 + level (fura-2AM) and SNARE protein expression (VAMP-2, SNAP-25 and syntaxin-1A). Cholesterol was depleted by incubating the islets with increasing concentrations (0–10 mmol/l) of methyl-beta-cyclodextrin (MβCD).

Results

The first and second phases of glucose-stimulated insulin secretion (GSIS) were lower in LDLR−/− than in WT islets, paralleled by an impairment of Ca2 + handling in the former. SNAP-25 and VAMP-2, but not syntaxin-1A, were reduced in LDLR−/− compared with WT islets. Removal of excess cholesterol from LDLR−/− islets normalized glucose- and tolbutamide-induced insulin release. Glucose-stimulated Ca2 + handling was also normalized in cholesterol-depleted LDLR−/− islets. Cholesterol removal from WT islets by 0.1 and 1.0 mmol/l MβCD impaired both GSIS and Ca2 + handling. In addition, at 10 mmol/l MβCD WT islet showed a loss of membrane integrity and higher DNA fragmentation.

Conclusion

Abnormally high (LDLR−/− islets) or low cholesterol content (WT islets treated with MβCD) alters both GSIS and Ca2 + handling. Normalization of cholesterol improves Ca2 + handling and insulin secretion in LDLR−/− islets.  相似文献   

18.

Aims

We have previously demonstrated that propyl gallate has a Ca2 + sensitizing effect on the force generation in membrane-permeabilized (skinned) cardiac muscle fibers. However, in vivo beneficial effects of propyl gallate as a novel Ca2 + sensitizer remain uncertain. In the present study, we aim to explore in vivo effects of propyl gallate.

Main methods

We compared effects of propyl gallate on ex vivo intact cardiac muscle fibers and in vivo hearts in healthy mice with those of pimobendan, a clinically used Ca2 + sensitizer. The therapeutic effect of propyl gallate was investigated using a mouse model of dilated cardiomyopathy (DCM) with reduced myofilament Ca2 + sensitivity due to a deletion mutation ΔK210 in cardiac troponin T.

Key findings

Propyl gallate, as well as pimobendan, showed a positive inotropic effect. Propyl gallate slightly increased the blood pressure without changing the heart rate in healthy mice, whereas pimobendan decreased the blood pressure probably through vasodilation via inhibition of phosphodiesterase and increased the heart rate. Propyl gallate prevented cardiac remodeling and systolic dysfunction and significantly improved the life-expectancy of knock-in mouse model of DCM with reduced myofilament Ca2 + sensitivity due to a mutation in cardiac troponin T. On the other hand, gallate, a similarly strong antioxidant polyphenol lacking Ca2 + sensitizing action, had no beneficial effects on the DCM mice.

Significance

These results suggest that propyl gallate might be useful for the treatment of inherited DCM caused by a reduction in the myofilament Ca2 + sensitivity.  相似文献   

19.

Background

Phospholipid scramblases are a group of four homologous proteins conserved from C. elegans to human. In human, two members of the scramblase family, hPLSCR1 and hPLSCR3 are known to bring about Ca2+ dependent translocation of phosphatidylserine and cardiolipin respectively during apoptotic processes. However, affinities of Ca2+/Mg2+ binding to human scramblases and conformational changes taking place in them remains unknown.

Methods

In the present study, we analyzed the Ca2+ and Mg2+ binding to the calcium binding motifs of hPLSCR1–4 and hPLSCR1 by spectroscopic methods and isothermal titration calorimetry.

Results

The results in this study show that (i) affinities of the peptides are in the order hPLSCR1  > hPLSCR3 > hPLSCR2 > hPLSCR4 for Ca2+ and in the order hPLSCR1 > hPLSCR2 > hPLSCR3 > hPLSCR4 for Mg2+, (ii) binding of ions brings about conformational change in the secondary structure of the peptides. The affinity of Ca2+ and Mg2+ binding to protein hPLSCR1 was similar to that of the peptide I. A sequence comparison shows the existence of scramblase-like motifs among other protein families.

Conclusions

Based on the above results, we hypothesize that the Ca2+ binding motif of hPLSCR1 is a novel type of Ca2+ binding motif.

General significance

Our findings will be relevant in understanding the calcium dependent scrambling activity of hPLSCRs and their biological function.  相似文献   

20.

Background

A major challenge when creating interfaces for the nervous system is to translate between the signal carriers of the nervous system (ions and neurotransmitters) and those of conventional electronics (electrons).

Scope of review

Organic conjugated polymers represent a unique class of materials that utilizes both electrons and ions as charge carriers. Based on these materials, we have established a series of novel communication interfaces between electronic components and biological systems. The organic electronic ion pump (OEIP) presented in this review is made of the polymer–polyelectrolyte system poly(3,4-ethylenedioxythiophene):poly(styrenesulfonate) (PEDOT:PSS). The OEIP translates electronic signals into electrophoretic migration of ions and neurotransmitters.

Major conclusions

We demonstrate how spatio-temporally controlled delivery of ions and neurotransmitters can be used to modulate intracellular Ca2 + signaling in neuronal cells in the absence of convective disturbances. The electronic control of delivery enables strict control of dynamic parameters, such as amplitude and frequency of Ca2 + responses, and can be used to generate temporal patterns mimicking naturally occurring Ca2 + oscillations. To enable further control of the ionic signals we developed the electrophoretic chemical transistor, an analog of the traditional transistor used to amplify and/or switch electronic signals. Finally, we demonstrate the use of the OEIP in a new “machine-to-brain” interface by modulating brainstem responses in vivo.

General significance

This review highlights the potential of communication interfaces based on conjugated polymers in generating complex, high-resolution, signal patterns to control cell physiology. We foresee widespread applications for these devices in biomedical research and in future medical devices within multiple therapeutic areas. This article is part of a Special Issue entitled Organic Bioelectronics—Novel Applications in Biomedicine.  相似文献   

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