UMLS:C0011570 - FACTA Search

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Query: UMLS:C0011570 (depression)
172,036 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

This study was designed to test the hypothesis that blockade of the renin-angiotensin system improves cardiac function in congestive heart failure by preventing changes in gene expression of sarcoplasmic reticulum (SR) proteins. We employed rats with myocardial infarction (MI) to examine effects of an angiotensin-converting enzyme inhibitor, imidapril, on SR Ca(2+) transport, protein content, and gene expression. Imidapril (1 mg.kg(-1).day(-1)) was given for 4 wk starting 3 wk after coronary artery occlusion. Infarcted rats exhibited a fourfold increase in left ventricular end-diastolic pressure, whereas rates of pressure development and decay were decreased by 60 and 55%, respectively. SR Ca(2+) uptake and Ca(2+) pump ATPase, as well as Ca(2+) release and ryanodine receptor binding activities, were depressed in the failing hearts; protein content and mRNA levels for Ca(2+) pump ATPase, phospholamban, and ryanodine receptor were also decreased by approximately 55-65%. Imidapril treatment of infarcted animals improved cardiac performance and attenuated alterations in SR Ca(2+) pump and Ca(2+) release activities. Changes in protein content and mRNA levels for SR Ca(2+) pump ATPase, phospholamban, and ryanodine receptor were also prevented by imidapril treatment. Beneficial effects of imidapril on cardiac function and SR Ca(2+) transport were not only seen at different intervals of MI but were also simulated by another angiotensin-converting enzyme inhibitor, enalapril, and an ANG II receptor antagonist, losartan. These results suggest that blockade of the renin-angiotensin system may increase the abundance of mRNA for SR proteins and, thus, may prevent the depression in SR Ca(2+) transport and improve cardiac function in congestive heart failure due to MI.
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PMID:Sarcoplasmic reticulum Ca2+ transport and gene expression in congestive heart failure are modified by imidapril treatment. 1557 37

The normally positive force- and Ca2+ -frequency responses (FFR and CaFR) are inverted in heart failure (HF); whether oxidative stress contributes to these abnormalities is unknown. We evaluated the impact of acute and prolonged oxidative stress on contraction and Ca2+ handling in adult rat cardiomyocytes. Acute (30 min) exposure to H2O2 (100 microM) induced a twofold increase (P<0.025) in intracellular oxyradicals together with contractile depression despite preservation of the Ca2+ transient and the FFR and CaFR to 3 Hz, indicating reduced myofilament Ca2+ responsiveness. In contrast, prolonged (24 h) exposure to the copper-zinc superoxide dismutase inhibitor diethyldithiocarbamic acid (DDC, 1 microM) similarly augmented oxyradicals but also increased cell size, and contraction and Ca2+ transient duration (P<0.025). DDC-treated myocytes displayed inverted FFRs and attenuated (though still positive) CaFRs as compared to control, indicating reduced myofilament Ca2+ responsiveness coupled with altered Ca2+ handling. Protein levels of the Na+ -Ca2+ exchanger (NCX), sarcoplasmic reticular (SR) Ca2+ ATPase (SERCA2), and serine-16 phosphorylated phospholamban (pSer16-PLB) were increased (P<0.025), whereas dihydropyridine receptor abundance was decreased. Total PLB and ryanodine receptor protein expression were unchanged. Caffeine-induced Ca2+ release showed increased NCX activity (P<0.025) without changes in total releasable SR Ca2+, suggesting compensatory changes in SERCA2 and pSer16-PLB to maintain SR Ca2+ load. The superoxide scavenger Tiron attenuated these effects. Thus, acute oxyradical exposure rapidly depresses myofibrillar Ca2+ responsiveness. Prolonged oxidative stress further induces alterations in Ca2+ handling that combined with extant reductions in myofibrillar responsiveness invert the FFR. With regard to Ca2+ handling, reduced transsarcolemmal Ca2+ flux rather than reduced SR Ca2+ uptake was the primary determinant of a negative FFR. Analogous changes may be operative in HF, a state characterized by both oxidative stress and Ca2+ dysregulation.
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PMID:Prolonged oxidative stress inverts the cardiac force-frequency relation: role of altered calcium handling and myofilament calcium responsiveness. 1628 76

The smooth endoplasmic reticulum (SER) is a well-characterized buffer and source of Ca2+ in both axonal and dendritic compartments of neurons. Ca2+ release from the SER can be evoked by stimulation of the ryanodine receptor or the inositol (1,4,5)-trisphosphate [Ins(1,4,5)P3] receptor. Both receptors can couple to the activation of neurotransmitter-gated receptors and voltage-gated Ca2+ channels on the plasma membrane, thus enabling the SER to discriminate between different types of neuronal activity. In axonal terminals, Ca2+-induced Ca2+ release (CICR) mediates spontaneous, evoked and facilitated neurotransmission. Store release might also regulate the mobilization and recycling of synaptic vesicles. In the dendritic compartment, the distribution of Ins(1,4,5)P3 receptors and ryanodine receptors influences the intracellular encoding of neuronal activity. Thus, the functionality of the Ca2+ store can affect both the polarity and the spatial extent of Ca2+-dependent shifts in synaptic efficacy. In hippocampal neurons, for example, CICR in the spine heads underlies homosynaptic plasticity, whereas heterosynaptic plasticity is mediated by Ins(1,4,5)P3-dependent Ca2+ signalling. Purkinje neurons primarily express Ins(1,4,5)P3 receptors in the spine heads, and long-term depression of synaptic efficacy is crucially dependent on Ins(1,4,5)P3.
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PMID:The role of the endoplasmic reticulum Ca2+ store in the plasticity of central neurons. 1641 23

Pathophysiological changes in arterial smooth muscle structure and function occur with aging and there are a number of reports illustrating reductions in vascular responsiveness with aging. While much is known about arterial remodeling and functional adaptations with aging, very little is known about the biophysical adaptations in individual arterial myocytes. Cytosolic Ca2+ signaling, involving activation of L-type Ca2+ channels on the plasma membrane as well as InsP3 and ryanodine receptors on the sarcoplasmic reticulum, is integral to vascular tone and reactivity. Thus, we tested the hypothesis that aging results in reductions in the functional expression of L-type channels and temporal aspects of ryanodine receptor and InsP3 receptor Ca2+ signaling, in mesenteric arterial smooth muscle cells isolated from 6 and 30 months old C57Bl/6 mice. Comparisons of L-type current activity were made using dialyzed, whole-cell voltage-clamp techniques and Ba2+ as charge carrier. Ca2+ signaling was measured using fura-2 fluorescence microscopy techniques. Cell morphological changes were also investigated using electrophysiological and immunocytochemical approaches. The amplitudes of L-type Ca2+ currents were increased in older mice, but this was associated with membrane surface area increases of approximately 50%, due to increases in cell length not cell width. Consequently, L-type Ca2+ current densities were preserved with age, indicating functional channel expression was unchanged. In contrast, aging was associated with decrements in Ca2+ signaling in response to either ryanodine receptor stimulation by caffeine or InsP3 receptor activation with phenylephrine. These changes with aging may be related to the previously reported depression in myogenic reactivity.
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PMID:Effects of aging on Ca2+ signaling in murine mesenteric arterial smooth muscle cells. 1641 46

Cardiovascular disease is the leading cause of death in the diabetic population. However, molecular mechanisms underlying diabetic cardiomyopathy remain unclear. We analyzed Ca2+-induced Ca2+ release and excitation-contraction coupling in db/db obese type 2 diabetic mice and their control littermates. Echocardiography showed a systolic dysfunction in db/db mice. Two-photon microscopy identified intracellular calcium concentration ([Ca2+]i) transient decrease in cardiomyocytes within the whole heart, which was also found in isolated myocytes by confocal microscopy. Global [Ca2+]i transients are constituted of individual Ca2+ sparks. Ca2+ sparks in db/db cardiomyocytes were less frequent than in +/+ myocytes, partly because of a depression in sarcoplasmic reticulum Ca2+ load but also because of a reduced expression of ryanodine receptor Ca2+ channels (RyRs), revealed by [3H]ryanodine binding assay. Ca2+ efflux through Na+/Ca2+ exchanger was increased in db/db myocytes. Calcium current, I(Ca), triggers sarcoplasmic reticulum Ca2+ release and is also involved in sarcoplasmic reticulum Ca2+ refilling. Macroscopic I(Ca) was reduced in db/db cells, but single Ca2+ channel activity was similar, suggesting that diabetic myocytes express fewer functional Ca2+ channels, which was confirmed by Western blots. These results demonstrate that db/db mice show depressed cardiac function, at least in part, because of a general reduction in the membrane permeability to Ca2+. As less Ca2+ enters the cell through I(Ca), less Ca2+ is released through RyRs.
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PMID:Mechanisms of [Ca2+]i transient decrease in cardiomyopathy of db/db type 2 diabetic mice. 1650 22

This study investigated the influence of chronic beta(3)-adrenoceptor deficiency on myocardial function. Therefore, we investigated Ca(2+)-regulatory proteins, SERCA 2a activity, and myofibrillar and mitochondrial function in hearts of wild-type (WT, n=7) and beta(3)-adrenoceptor knockout mice (beta(3)-KNO, n=7). Morphometric heart analysis showed no difference between WT and beta(3)-KNO. No alterations were observed for the protein expression of the ryanodine receptor or phospholamban. However, in beta(3)-KNO mice, protein expression of SERCA 2a and phospholamban phosphorylation were significantly increased. These changes were accompanied by an increased SERCA 2a activity in beta(3)-KNO. Alterations in phospholamban phosphorylation were independent of alterations in beta(1)/beta(2)-adrenoceptor distribution and protein expression of G proteins in beta(3)-KNO. Measurement of myofibrillar Ca(2+) sensitivity showed no difference in the Ca(2+)/force relation for WT and beta(3)-KNO. The same seems to hold true for mitochondrial function since the protein expressions of cytochrome c, uncoupling protein 3 and cytochrome c oxidase subunit IV were similar in WT and beta(3)-KNO. The conclusion is that depression of beta(3)-adrenergic stimulation may modulate the protein expression of SERCA 2a and phospholamban phosphorylation, thereby improving sarcoplasmic reticulum Ca(2+) uptake. Thus, beta(3)-adrenergic depression may be a therapeutic aim in situations of impaired SERCA 2a activity, e.g. for the treatment of heart failure.
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PMID:Increased Ca2+ sensitivity and protein expression of SERCA 2a in situations of chronic beta3-adrenoceptor deficiency. 1702 99

Functional crosstalk between cell-surface and intracellular ion channels plays important roles in excitable cells and is structurally supported by junctophilins (JPs) in muscle cells. Here, we report a novel form of channel crosstalk in cerebellar Purkinje cells (PCs). The generation of slow afterhyperpolarization (sAHP) following complex spikes in PCs required ryanodine receptor (RyR)-mediated Ca(2+)-induced Ca(2+) release and the subsequent opening of small-conductance Ca(2+)-activated K(+) (SK) channels in somatodendritic regions. Despite the normal expression levels of these channels, sAHP was abolished in PCs from mutant mice lacking neural JP subtypes (JP-DKO), and this defect was restored by exogenously expressing JPs or enhancing SK channel activation. The stimulation paradigm for inducing long-term depression (LTD) at parallel fiber-PC synapses adversely established long-term potentiation in the JP-DKO cerebellum, primarily due to the sAHP deficiency. Furthermore, JP-DKO mice exhibited impairments of motor coordination and learning, although normal cerebellar histology was retained. Therefore, JPs support the Ca(2+)-mediated communication between voltage-gated Ca(2+) channels, RyRs and SK channels, which modulates the excitability of PCs and is fundamental to cerebellar LTD and motor functions.
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PMID:Junctophilin-mediated channel crosstalk essential for cerebellar synaptic plasticity. 1734 45

Activity-dependent changes in synaptic strength such as long-term potentiation (LTP) and long-term depression (LTD) are considered to be cellular mechanisms underlying learning and memory. Strengthening of a synapse for a few seconds or minutes is termed short-term potentiation (STP) and is normally unable to take part in the processes of synaptic tagging/capture due to its inability to set the "synaptic tags." Here, we report that priming of synapses with ryanodine receptor agonists such as ryanodine (10 microM) or caffeine (10 mM) facilitates subsequent synaptic tagging/capture, enabling an STP protocol to establish a late-LTP in response to strong tetanization of a heterosynaptic input. We identified calcium/calmodulin-dependent protein kinase II (CaMKII) as mediating the primed synaptic tag setting, which persisted for 1 h. We also identified protein kinase Mzeta (PKMzeta), presumably captured from the strongly tetanized heterosynaptic input, as a plasticity-related protein maintaining the LTP at the tagged synapses. In addition, synaptic tags in primed STP were erased or interfered with by delivering low-frequency depotentiating stimulation 5 or 10 min after its induction, thus preventing capture of newly synthesized proteins. These data reveal a novel form of metaplasticity, whereby ryanodine receptor activation lowers the threshold for subsequent synaptic tagging/capture, thus priming weakly activated synapses for heterosynaptic interactions that promote long-term functional plasticity.
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PMID:Priming of short-term potentiation and synaptic tagging/capture mechanisms by ryanodine receptor activation in rat hippocampal CA1. 1922 1

Alzheimer's disease (AD) is a progressive neurodegenerative disorder caused by an increase in amyloid metabolism. The calcium hypothesis of AD explores how activation of the amyloidogenic pathway may function to remodel the neuronal Ca(2+) signaling pathways responsible for cognition. Hydrolysis of the beta-amyloid precursor protein (APP) yields two products that can influence Ca(2+) signaling. Firstly, the amyloids released to the outside form oligomers that enhance the entry of Ca(2+) that is pumped into the endoplasmic reticulum (ER). An increase in the luminal level of Ca(2+) within the ER enhances the sensitivity of the ryanodine receptors (RYRs) to increase the amount of Ca(2+) being released from the internal stores. Secondly, the APP intracellular domain may alter the expression of key signaling components such as the RYR. It is proposed that this remodeling of Ca(2+) signaling will result in the learning and memory deficits that occur early during the onset of AD. In particular, the Ca(2+) signaling remodeling may erase newly acquired memories by enhancing the mechanism of long-term depression that depends on activation of the Ca(2+)-dependent protein phosphatase calcineurin. The alteration in Ca(2+) signaling will also contribute to the neurodegeneration that characterizes the later stages of dementia.
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PMID:Calcium hypothesis of Alzheimer's disease. 1979 32

Central glutamate neurotransmission has been postulated to play a role in pathophysiology of depression and in the mechanism of antidepressants. The present study was undertaken to elucidate the effect and the possible mechanism of bupropion, an atypical antidepressant, on endogenous glutamate release in nerve terminals of rat cerebral cortex (synaptosomes). Result showed that bupropion exhibited a dose-dependent inhibition of 4-aminopyridine (4-AP)-evoked release of glutamate. The effect of bupropion on the evoked glutamate release was prevented by the chelating the intrasynaptosomal Ca(2+) ions, and by the vesicular transporter inhibitor, but was insensitive to the glutamate transporter inhibitor. Bupropion decreased depolarization-induced increase in [Ca(2+)](C), whereas it did not alter the resting synaptosomal membrane potential or 4-AP-mediated depolarization. The effect of bupropion on evoked glutamate release was abolished by the N-, P- and Q-type Ca(2+) channel blocker, but not by the ryanodine receptor blocker, or the mitochondrial Na(+)/Ca(2+) exchanger blocker. In addition, the inhibitory effect of bupropion on evoked glutamate release was prevented by the mitogen-activated/extracellular signal-regulated kinase kinase (MEK) inhibitors. Western blot analyses showed that bupropion significantly decreased the 4-AP-induced phosphorylation of extracellular signal-regulated kinase 1 and 2 (ERK1/2), and this effect also was blocked by MEK inhibitor. These results are the first to suggest that, in rat cerebrocortical nerve terminals, bupropion suppresses voltage-dependent Ca(2+) channel and MEK/ERK activity and in so doing inhibits evoked glutamate release. This finding may provide important information regarding the beneficial effects of bupropion in the brain.
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PMID:Inhibition of glutamate release by bupropion in rat cerebral cortex nerve terminals. 2121 68

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