Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0345904 (liver cancer)
 15,188 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Voltage-gated L-type Ca(2+) channels (LCCs) provide Ca(2+) ingress into cardiac myocytes and play a key role in intracellular Ca(2+) homeostasis and excitation-contraction coupling. We investigated the effects of a constitutive increase of LCC density on Ca(2+) signaling in ventricular myocytes from 4-month-old transgenic (Tg) mice overexpressing the alpha(1) subunit of LCC in the heart. At this age, cells were somewhat hypertrophic as reflected by a 20% increase in cell capacitance relative to those from nontransgenic (Ntg) littermates. Whole cell I(Ca) density in Tg myocytes was elevated by 48% at 0 mV compared with the Ntg group. Single-channel analysis detected an increase in LCC density with similar conductance and gating properties. Although the overexpressed LCCs triggered an augmented SR Ca(2+) release, the "gain" function of EC coupling was uncompromised, and SR Ca(2+) content, diastolic cytosolic Ca(2+), and unitary properties of Ca(2+) sparks were unchanged. Importantly, the enhanced I(Ca) entry and SR Ca(2+) release were associated with an upregulation of the Na(+)-Ca(2+) exchange activity (indexed by the half decay time of caffeine-elicited Ca(2+) transient) by 27% and SR Ca(2+) recycling by approximately 35%. Western analysis detected a 53% increase in the Na(+)-Ca(2+) exchanger expression but no change in the abundance of ryanodine receptor (RyR), SERCA2, and phospholamban. Analysis of I(Ca) kinetics suggested that SR Ca(2+) release-dependent inactivation of LCCs remains intact in Tg cells. Thus, in spite of the modest cardiac hypertrophy, the overexpressed LCCs form functional coupling with RyRs, preserving both orthograde and retrograde Ca(2+) signaling between LCCs and RyRs. These results also suggest that a modest but sustained increase in Ca(2+) influx triggers a coordinated remodeling of Ca(2+) handling to maintain Ca(2+) homeostasis.
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PMID:Ca(2+) signaling in cardiac myocytes overexpressing the alpha(1) subunit of L-type Ca(2+) channel. 1183 10

We investigated the effect of combined inhibition of oxidative and glycolytic metabolism on L-type Ca(2+) channels (LCCs) and Ca(2+) spikes in isolated patch-clamped rabbit ventricular myocytes. Metabolic inhibition (MI) reduced LCC open probability, increased null probability, increased first latency, and decreased open time but left conductance unchanged. These results explain the reduction in macroscopic Ca(2+) current observed during MI. MI also produced a gradual reduction in action potential duration at 90% repolarization (APD(90)), a clear decline in spike probability, and an increase in spike latency and variance. These effects are consistent with the changes we observed in LCC activity. MI had no effect on the amplitude or time to peak of Ca(2+) spikes until APD(90) reached 10% of control, suggesting preserved sarcoplasmic reticulum Ca(2+) stores and ryanodine receptor (RyR) conductance in those couplons that remained functioning. Ca(2+) spikes disappeared completely when APD(90) reached <2% of control, although in two cells, spikes were reactivated in a highly synchronized fashion by very short action potentials. This reactivation is probably due to the increased driving force for Ca(2+) entry through a reduced number of LCCs that remain open during early repolarization. The enlarged single channel flux produced by rapid repolarization is apparently sufficient to trigger RyRs whose Ca(2+) sensitivity is likely reduced by MI. We suggest that loss of coupling fidelity during MI is explained by loss of LCC activity (possibly mediated by Ca(2+)-calmodulin kinase II activity). In addition, the results are consistent with loss of RyR activity, which can be mitigated under conditions likely to enlarge the trigger.
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PMID:Effect of metabolic inhibition on couplon behavior in rabbit ventricular myocytes. 1802 4

Mutations of Ca(2+)-activated proteases (calpains) cause muscular dystrophies. Nevertheless, the specific role of calpains in Ca(2+) signalling during the onset of dystrophies remains unclear. We investigated Ca(2+) handling in skeletal cells from calpain 3-deficient mice. [Ca(2+)](i) responses to caffeine, a ryanodine receptor (RyR) agonist, were decreased in -/- myotubes and absent in -/- myoblasts. The -/- myotubes displayed smaller amplitudes of the Ca(2+) transients induced by cyclopiazonic acid in comparison to wild type cells. Inhibition of L-type Ca(2+) channels (LCC) suppressed the caffeine-induced [Ca(2+)](i) responses in -/- myotubes. Hence, the absence of calpain 3 modifies the sarcoplasmic reticulum (SR) Ca(2+) release, by a decrease of the SR content, an impairment of RyR signalling, and an increase of LCC activity. We propose that calpain 3-dependent proteolysis plays a role in activating support proteins of intracellular Ca(2+) signalling at a stage of cellular differentiation which is crucial for skeletal muscle regeneration.
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PMID:Alteration of sarcoplasmic reticulum ca release in skeletal muscle from calpain 3-deficient mice. 2030 May 93

Paraptosis is a programmed cell death which is morphologically and biochemically different from apoptosis. In this study, we have investigated the role of Ca(2+) in hesperidin-induced paraptotic cell death in HepG2 cells. Increase in mitochondrial Ca(2+) level was observed in hesperidin treated HepG2 cells but not in normal liver cancer cells. Inhibition of inositol-1,4,5-triphosphate receptor (IP3 R) and ryanodine receptor also block the mitochondrial Ca(2+) accumulation suggesting that the release of Ca(2+) from the endoplasmic reticulum (ER) may probably lead to the increase in mitochondrial Ca(2+) level. Pretreatment with ruthenium red (RuRed), a Ca(2+) uniporter inhibitor inhibited the hesperidin-induced mitochondrial Ca(2+) overload, swelling of mitochondria, and cell death in HepG2 cells. It has also been demonstrated that mitochondrial Ca(2+) influxes act upstream of ROS and mitochondrial superoxide production. The increased ROS production further leads to mitochondrial membrane loss in hesperidin treated HepG2 cells. Taken together our results show that IP3 R and ryanodine receptor mediated release of Ca(2+) from the ER and its subsequent influx through the uniporter into mitochondria contributes to hesperidin-induced paraptosis in HepG2 cells.
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PMID:Mitochondrial Dysfunction and Ca(2+) Overload Contributes to Hesperidin Induced Paraptosis in Hepatoblastoma Cells, HepG2. 2649 5