scholarly journals Sex-related effects on diabetes-induced alterations in calcium release in the rat heart

2007 ◽  
Vol 293 (6) ◽  
pp. H3584-H3592 ◽  
Author(s):  
Nazmi Yaras ◽  
Erkan Tuncay ◽  
Nuhan Purali ◽  
Babur Sahinoglu ◽  
Guy Vassort ◽  
...  
Keyword(s):  
Calcium Release ◽  
Binding Protein ◽  
Ryanodine Receptors ◽  
Left Ventricular ◽  
Adult Rats ◽  
Fk506 Binding Protein ◽  
Pressure Development ◽  
Spatiotemporal Parameters ◽  
Intracellular Ca ◽  
Developed Pressure

The present study was designed to determine whether the properties of local Ca2+ release and its related regulatory mechanisms might provide insight into the role of sex differences in heart functions of control and streptozotocin-induced diabetic adult rats. Left ventricular developed pressure, the rates of pressure development and decay (±dP/d t), basal intracellular Ca2+ level ([Ca2+]i), and spatiotemporal parameters of [Ca2+]i transients were found to be similar in male and female control rats. However, spatiotemporal parameters of Ca2+ sparks in cardiomyocytes isolated from control females were significantly larger and slower than those in control males. Diabetes reduced left ventricular developed pressure to a lower extent in females than in males, and the diabetes-induced depressions in both +dP/d t and −dP/d t were less in females than in males. Diabetes elicited a smaller reduction in the amplitude of [Ca2+]i transients in females than in males, a smaller reduction in sarcoplasmic reticulum-Ca2+ load, and less increase in basal [Ca2+]i. Similarly, the elementary Ca2+ events and their control proteins were clearly different in both sexes, and these differences were more marked in diabetes. Diabetes-induced depression of the Ca2+ spark amplitude was significantly less in females than in matched males. Levels of cardiac ryanodine receptors (RyR2) and FK506-binding protein 12.6 in control females were significantly higher than those shown in control males. Diabetes induced less RyR2 phosphorylation and FK506-binding protein 12.6 unbinding in females. Moreover, total and free sulfhydryl groups were significantly less reduced, and PKC levels were less increased, in diabetic females than in diabetic males. The present data related to local Ca2+ release and its related proteins describe some of the mechanisms that may underlie sex-related differences accounting for females to have less frequent development of cardiac diseases.

Modulation of type-1 Ins(1,4,5)P3 receptor channels by the FK506-binding protein, FKBP12

2002 ◽  
Vol 361 (2) ◽  
pp. 401-407 ◽  
Author(s):  
Sheila L. DARGAN ◽  
Edward J. A. LEA ◽  
Alan P. DAWSON
Keyword(s):  
Lipid Bilayers ◽  
Calcium Release ◽  
Single Channel ◽  
Binding Protein ◽  
Ryanodine Receptors ◽  
Fk506 Binding Protein ◽  
Single Channel Activity ◽  
And Function ◽  
First Time

FK506-binding protein (FKBP12) is highly expressed in neuronal tissue, where it is proposed to localize calcineurin to intracellular calcium-release channels, ryanodine receptors and Ins(1,4,5)P3 receptors (InsP3Rs). The effects of FKBP12 on ryanodine receptors have been well characterized but the nature and function of binding of FKBP12 to InsP3R is more controversial, with evidence for and against a tight interaction between these two proteins. To investigate this, we incorporated purified type-1 InsP3R from rat cerebellum into planar lipid bilayers to monitor the effects of exogenous recombinant FKBP12 on single-channel activity, using K+ as the current carrier. Here we report for the first time that FKBP12 causes a substantial change in single-channel properties of the type-1 InsP3R, specifically to increase the amount of time the channel spends in a fully open state. In the presence of ATP, FKBP12 can also induce co-ordinated gating with neighbouring receptors. The effects of FKBP12 were reversed by FK506. We also present data showing that rapamycin, at sub-optimal concentrations of Ins(2,4,5)P3, decreases the rate of calcium release from cerebellar microsomes. These results provide evidence for a direct functional interaction between FKBP12 and the type-1 InsP3R.

Testosterone-augmented contractile responses to α1- and β1-adrenoceptor stimulation are associated with increased activities of RyR, SERCA, and NCX in the heart

2009 ◽  
Vol 296 (4) ◽  
pp. C766-C782 ◽  
Author(s):  
Sharon Tsang ◽  
Stanley S. C. Wong ◽  
Song Wu ◽  
Gennadi M. Kravtsov ◽  
Tak-Ming Wong
Keyword(s):  
Ventricular Myocytes ◽  
Left Ventricular ◽  
Contractile Responses ◽  
Adrenoceptor Antagonist ◽  
Cardiac Contractile ◽  
Plasmic Reticulum ◽  
Adrenoceptor Agonist ◽  
Intracellular Ca ◽  
Developed Pressure ◽  
Stimulation Of

We hypothesized that testosterone at physiological levels enhances cardiac contractile responses to stimulation of both α1- and β1-adrenoceptors by increasing Ca2+ release from the sarcoplasmic reticulum (SR) and speedier removal of Ca2+ from cytosol via Ca2+-regulatory proteins. We first determined the left ventricular developed pressure, velocity of contraction and relaxation, and heart rate in perfused hearts isolated from control rats, orchiectomized rats, and orchiectomized rats without and with testosterone replacement (200 μg/100 g body wt) in the presence of norepinephrine (10−7 M), the α1-adrenoceptor agonist phenylephrine (10−6 M), or the nonselective β-adrenoceptor agonist isoprenaline (10−7 M) in the presence of 5 × 10−7 M ICI-118,551, a β2-adrenoceptor antagonist. Next, we determined the amplitudes of intracellular Ca2+ concentration transients induced by electrical stimulation or caffeine, which represent, respectively, Ca2+ release via the ryanodine receptor (RyR) or releasable Ca2+ in the SR, in ventricular myocytes isolated from the three groups of rats. We also measured 45Ca2+ release via the RyR. We then determined the time to 50% decay of both transients, which represents, respectively, Ca2+ reuptake by sarco(endo)plasmic reticulum Ca2+-ATPase (SERCA) and removal via the sarcolemmal Na+/Ca2+ exchanger (NCX). We correlated Ca2+ removal from the cytosol with activities of SERCA and its regulator phospholamban as well as NCX. The results showed that testosterone at physiological levels enhanced positive inotropic and lusitropic responses to stimulation of α1- and β1-adrenoceptors via the androgen receptor. The increased contractility and speedier relaxation were associated with increased Ca2+ release via the RyR and faster Ca2+ removal out of the cytosol via SERCA and NCX.

Abstract 18: Increasing in vivo Apoa1/HDL Levels Negates the Cardiotoxic Effects of Doxorubicin, and Involves Signalling Through SR-BI, PI3K, and AKT1

2015 ◽  
Vol 117 (suppl_1) ◽  
Author(s):  
Kristina Durham ◽  
Cyrus Thomas ◽  
Bernardo L Trigatti
Keyword(s):  
Fold Increase ◽  
Left Ventricular ◽  
Cardiomyocyte Apoptosis ◽  
Cross Sectional ◽  
Over Expression ◽  
Pressure Development ◽  
Reduced Rate ◽  
Induced Apoptosis ◽  
Developed Pressure

Doxorubicin (DOX) is a clinically used anti-tumor drug, though the use of DOX is limited by its potent cardiotoxic side effect that can lead to heart failure. HDL protects isolated cardiomyocytes against DOX induced apoptosis, though whether this effect translates in vivo has yet to be determined. Here we assess whether ApoA1/HDL overexpression can protect mice in vivo against DOX induced cardiotoxicity, and explore the intracellular signalling mechanisms involved in protection. Mice overexpressing human ApoA1 (ApoA1tg/tg) and ApoA1+/+ mice were treated chronically with DOX, and effects on cardiac function and cardiomyocyte health were assessed. Over expression of human ApoA1 in mice corresponded to ~2.5 fold increase in plasma HDL-C as compared to ApoA1+/+ mice. Following 5 weekly injections of 5mg/kg DOX, ApoA1+/+ mice displayed cardiac dysfunction as evidenced by reduced left ventricular developed pressure, and reduced rate of pressure development. In contrast, left ventricular function was maintained following DOX treatment in ApoA1tg/tg mice. Histological analysis revealed reduced cardiomyocyte cross-sectional area and increased cardiomyocyte apoptosis following DOX treatment in ApoA1+/+ mice. ApoA1tg/tg mice, on the other hand, were protected against DOX induced cardiomyocyte atrophy and apoptosis. Interestingly, pAKT:tAKT was reduced in ApoA1+/+ by treatment with DOX, but the ratio was maintained in ApoA1tg/tg mice. We evaluated the roles of SR-BI, PI3K, and AKT1/2 in the signalling cascade of HDL in neonatal mouse cardiomyocytes and human immortalized ventricular cardiomyocytes. Through inhibition of AKT and PI3K, and knockdown or knockout of SR-BI, AKT1, and AKT2, we demonstrated that SR-BI, PI3K and AKT1 are required for HDL mediated protection against DOX induced cardiomyocyte apoptosis. Our results provide evidence for ApoA1 mediated protection against DOX cardiotoxicity in vivo and demonstrate the roles of SR-BI, PI3K, and AKT1 as mediators in the protective effect.

The Ryanodine Receptor/Calcium Release Channel and its Interaction Partners

1998 ◽  
Vol 4 (S2) ◽  
pp. 968-969
Author(s):  
Terry Wagenknecht ◽  
Montserrat Samso
Keyword(s):  
Calcium Release ◽  
Striated Muscle ◽  
Ryanodine Receptors ◽  
Three Dimensional ◽  
Structural Complexity ◽  
Body Representation ◽  
Calcium Release Channel ◽  
Release Channel ◽  
Fk506 Binding Protein ◽  
Dimensional Reconstruction

Ryanodine receptors (RyRs) function as the major intracellular calcium release channels in striated muscle, where they also play a central role in excitation-contraction (e-c) coupling, the signal transduction process by which neuron-induced depolarization of the muscle plasma membrane leads to release of Ca from the sarcoplasmic reticulum. Structurally, RyRs are the largest ion channels known, being composed of 4 identical large subunits (565 kDa). In situ, RyRs interact with numerous proteins that are essential for e-c coupling or regulation thereof. Some of these ligands include calmodulin, a 12-kDa FK506-binding protein (FKBP, an immunophi1 in), calsequestrin, triadin, and the dihydropyridine receptor (DHPR).Detergent-solubilized, purified RyRs appear to retain their native structure as assessed by electron cryo-microscopy, and are amenable to three-dimensional reconstruction by single-particle image processing techniques. In Fig. 1, a solid-body representation of the reconstructed skeletal muscle RyR shows the structural complexity that is revealed at moderate resolutions (3-4 nm).

Protective effects of adenosine in the perfused rat heart: changes in metabolism and intracellular ion homeostasis

1993 ◽  
Vol 264 (4) ◽  
pp. C986-C994 ◽  
Author(s):  
T. A. Fralix ◽  
E. Murphy ◽  
R. E. London ◽  
C. Steenbergen
Keyword(s):  
Cell Injury ◽  
Recovery Of Function ◽  
Ion Homeostasis ◽  
High Energy ◽  
Left Ventricular ◽  
Protective Effects ◽  
Intracellular Ca ◽  
Developed Pressure ◽  
High Energy Phosphate Metabolism ◽  
Glycolytic Rate

Increased concentrations of intracellular H+, Na+, and Ca2+ have been observed during ischemia, and these ionic alterations have been correlated with several indexes of cell injury in a number of studies. Recently, adenosine was proposed to play a role in ischemic preconditioning, since adenosine antagonists block the protective effects of these brief intermittent periods of ischemia and reflow. In this study we evaluated the protective effects of adenosine (20 microM) on high-energy phosphate metabolism, H+ and Ca2+ accumulation, and glycolytic rate during 30 min of no-flow ischemia. Adenosine was observed to slow the onset of contracture (7.0 +/- 0.9 min) and to improve left ventricular developed pressure (62 +/- 7% of initial) during reperfusion compared with untreated hearts (5.0 +/- 0.6 min and 18 +/- 5%, respectively). Intracellular Ca accumulation at the end of 30 min of ischemia was higher in the untreated (2,835 +/- 465 nM) than in the adenosine-treated (2,064 +/- 533 nM) hearts, while intracellular pH fell more in the untreated (5.85 +/- 0.17) than in the adenosine-treated hearts (6.27 +/- 0.16). Glycolytic rate and the rate of ATP decline were significantly attenuated in the adenosine-treated hearts during ischemia. Thus adenosine treatment slowed the rate of metabolism and delayed the accumulation of H+ and Ca2+ during ischemia, resulting in better recovery of function upon reflow.

Glibenclamide improves postischemic recovery of myocardial contractile function in trained and sedentary rats

2001 ◽  
Vol 91 (4) ◽  
pp. 1545-1554 ◽  
Author(s):  
Korinne N. Jew ◽  
Russell L. Moore
Keyword(s):  
Contractile Function ◽  
Ischemia Reperfusion ◽  
Left Ventricular ◽  
Treadmill Running ◽  
Sprague Dawley ◽  
Sprague Dawley Rats ◽  
Diastolic Stiffness ◽  
Pressure Development ◽  
Increased Sensitivity ◽  
Developed Pressure

In this study, we sought to determine whether there was any evidence for the idea that cardiac ATP-sensitive K+ (KATP) channels play a role in the training-induced increase in the resistance of the heart to ischemia-reperfusion (I/R) injury. To do so, the effects of training and an KATP channel blocker, glibenclamide (Glib), on the recovery of left ventricular (LV) contractile function after 45 min of ischemia and 45 min of reperfusion were examined. Female Sprague-Dawley rats were sedentary (Sed; n = 18) or were trained (Tr; n = 17) for >20 wk by treadmill running, and the hearts from these animals used in a Langendorff-perfused isovolumic LV preparation to assess contractile function. A significant increase in the amount of 72-kDa class of heat shock protein was observed in hearts isolated from Tr rats. The I/R protocol elicited significant and substantial decrements in LV developed pressure (LVDP), minimum pressure (MP), rate of pressure development, and rate of pressure decline and elevations in myocardial Ca2+ content in both Sed and Tr hearts. In addition, I/R elicited a significant increase in LV diastolic stiffness in Sed, but not Tr, hearts. When administered in the perfusate, Glib (1 μM) elicited a normalization of all indexes of LV contractile function and reductions in myocardial Ca2+content in both Sed and Tr hearts. Training increased the functional sensitivity of the heart to Glib because LVDP and MP values normalized more quickly with Glib treatment in the Tr than the Sed group. The increased sensitivity of Tr hearts to Glib is a novel finding that may implicate a role for cardiac KATP channels in the training-induced protection of the heart from I/R injury.

scholarly journals Bcl-2 and FKBP12 bind to IP3 and ryanodine receptors at overlapping sites: the complexity of protein–protein interactions for channel regulation

2015 ◽  
Vol 43 (3) ◽  
pp. 396-404 ◽  
Author(s):  
Tim Vervliet ◽  
Jan B. Parys ◽  
Geert Bultynck
Keyword(s):  
Protein Interactions ◽  
Hippocampal Neurons ◽  
Binding Protein ◽  
Ryanodine Receptors ◽  
B Cell Lymphoma ◽  
Experimental Models ◽  
Amino Acid Sequences ◽  
Protein Protein Interactions ◽  
Fk506 Binding Protein ◽  
Fk506 Binding Proteins

The 12- and 12.6-kDa FK506-binding proteins, FKBP12 (12-kDa FK506-binding protein) and FKBP12.6 (12.6-kDa FK506-binding protein), have been implicated in the binding to and the regulation of ryanodine receptors (RyRs) and inositol 1,4,5-trisphosphate receptors (IP3Rs), both tetrameric intracellular Ca2+-release channels. Whereas the amino acid sequences responsible for FKBP12 binding to RyRs are conserved in IP3Rs, FKBP12 binding to IP3Rs has been questioned and could not be observed in various experimental models. Nevertheless, conservation of these residues in the different IP3R isoforms and during evolution suggested that they could harbour an important regulatory site critical for IP3R-channel function. Recently, it has become clear that in IP3Rs, this site was targeted by B-cell lymphoma 2 (Bcl-2) via its Bcl-2 homology (BH)4 domain, thereby dampening IP3R-mediated Ca2+ flux and preventing pro-apoptotic Ca2+ signalling. Furthermore, vice versa, the presence of the corresponding site in RyRs implied that Bcl-2 proteins could associate with and regulate RyR channels. Recently, the existence of endogenous RyR–Bcl-2 complexes has been identified in primary hippocampal neurons. Like for IP3Rs, binding of Bcl-2 to RyRs also involved its BH4 domain and suppressed RyR-mediated Ca2+ release. We therefore propose that the originally identified FKBP12-binding site in IP3Rs is a region critical for controlling IP3R-mediated Ca2+ flux by recruiting Bcl-2 rather than FKBP12. Although we hypothesize that anti-apoptotic Bcl-2 proteins, but not FKBP12, are the main physiological inhibitors of IP3Rs, we cannot exclude that Bcl-2 could help engaging FKBP12 (or other FKBP isoforms) to the IP3R, potentially via calcineurin.

scholarly journals The Conserved Sites for the FK506-binding Proteins in Ryanodine Receptors and Inositol 1,4,5-Trisphosphate Receptors Are Structurally and Functionally Different

2001 ◽  
Vol 276 (50) ◽  
pp. 47715-47724 ◽  
Author(s):  
Geert Bultynck ◽  
Daniela Rossi ◽  
Geert Callewaert ◽  
Ludwig Missiaen ◽  
Vincenzo Sorrentino ◽  
...  
Keyword(s):  
Secondary Structure ◽  
Binding Site ◽  
Ryanodine Receptors ◽  
Site Directed Mutagenesis ◽  
Fk506 Binding Protein ◽  
Critical Residue ◽  
Inositol 1,4,5 Trisphosphate ◽  
Intracellular Ca ◽  
Α Helix ◽  
Type 3

We compared the interaction of the FK506-binding protein (FKBP) with the type 3 ryanodine receptor (RyR3) and with the type 1 and type 3 inositol 1,4,5-trisphosphate receptor (IP3R1 and IP3R3), using a quantitative GST-FKBP12 and GST-FKBP12.6 affinity assay. We first characterized and mapped the interaction of the FKBPs with the RyR3. GST-FKBP12 as well as GST-FKBP12.6 were able to bind ∼30% of the solubilized RyR3. The interaction was completely abolished by FK506, strengthened by the addition of Mg2+, and weakened in the absence of Ca2+but was not affected by the addition of cyclic ADP-ribose. By using proteolytic mapping and site-directed mutagenesis, we pinpointed Val2322, located in the central modulatory domain of the RyR3, as a critical residue for the interaction of RyR3 with FKBPs. Substitution of Val2322for leucine (as in IP3R1) or isoleucine (as in RyR2) decreased the binding efficiency and shifted the selectivity to FKBP12.6; substitution of Val2322for aspartate completely abolished the FKBP interaction. Importantly, the occurrence of the valylprolyl residue as α-helix breaker was an important determinant of FKBP binding. This secondary structure is conserved among the different RyR isoforms but not in the IP3R isoforms. A chimeric RyR3/IP3R1, containing the core of the FKBP12-binding site of IP3R1 in the RyR3 context, retained this secondary structure and was able to interact with FKBPs. In contrast, IP3Rs did not interact with the FKBP isoforms. This indicates that the primary sequence in combination with the local structural environment plays an important role in targeting the FKBPs to the intracellular Ca2+-release channels. Structural differences in the FKBP-binding site of RyRs and IP3Rs may contribute to the occurrence of a stable interaction between RyR isoforms and FKBPs and to the absence of such interaction with IP3Rs.

scholarly journals Akkermansia muciniphila secretome promotes α-synuclein aggregation in enteroendocrine cells

2021 ◽  
Author(s):  
Dionísio Pedro Amorim Neto ◽  
Beatriz Pelegrini Bosque ◽  
João Vitor Pereira de Godoy ◽  
Paulla Vieira Rodrigues ◽  
Dario Donoso Meneses ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Calcium Release ◽  
Ryanodine Receptors ◽  
Enteroendocrine Cells ◽  
Ros Generation ◽  
List Type ◽  
Functional Link ◽  
Akkermansia Muciniphila ◽  
Intracellular Ca

ABSTRACTThe notion that the gut microbiota play a role in neurodevelopment, behavior and outcome of neurodegenerative disorders is recently taking place. A number of studies have consistently reported a greater abundance of Akkermansia muciniphila in Parkinson’s disease (PD) fecal samples. Nevertheless, a functional link between A.muciniphila and sporadic PD remained unexplored. Here, we investigated whether A.muciniphila secretome could initiate the misfolding process of α-synuclein (αSyn) in enteroendocrine cells (EECs), which are part of the gut epithelium and possess many neuron-like properties. We found that A.muciniphila secretome is directly modulated by mucin, induces intracellular calcium (Ca2+) release, and causes increased mitochondrial Ca2+ uptake in EECs, which in turn leads to production of reactive oxygen species (ROS) and αSyn aggregation. However, these events were efficiently inhibited once we buffered mitochondrial Ca2+. Thereby, these molecular insights provided here offer evidence that bacterial secretome is capable of inducing αSyn aggregation in enteroendocrine cells.SYNOPSIS FIGURE DESCRIPTIONThe secretome isolated from the commensal gut bacterium Akkermansia muciniphila triggers intracellular Ca2+ signaling in enteroendocrine cells, leading to increased mitochondrial Ca2+ uptake. Mitochondrial Ca2+ overload leads to ROS generation culminating with αSyn phosphorylation and aggregation (left panel). All these events were inhibited once mitochondrial Ca2+ is buffered (right panel).Gram-negative gut bacterium Akkermansia muciniphila is consistently found more abundant in Parkinson’s disease patients.Akkermansia muciniphila protein secretome composition is directly modulated by mucin and induces an IP3-independent endoplasmic reticulum (ER)-calcium release in enteroendocrine cells.This Ca2+ release is triggered by direct activation of Ryanodine Receptors leading to increased mitochondrial Ca2+ uptake.Mitochondrial Ca2+ overload leads to ROS generation culminating with αSyn aggregation.Buffering mitochondrial Ca2+ efficiently inhibits A.muciniphila-induced αSyn aggregation in enteroendocrine cells.

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