Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.7.11.17 (CaMKII)
 4,029 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The preproendothelin-1 (preproET-1) gene is induced by thrombin after phosphorylation of nonreceptor protein tyrosine kinase pathways. This study investigated the contribution of Ca2+/calmodulin-dependent intracellular signaling cascades to this pathway and measured ET-1 mRNA levels by Northern blot analysis in human endothelial cells. Increased intracellular Ca2+ levels in response to Ca2+ ionophore or Ca2+ ATPase inhibitors tert-butylhydroquinone and thapsigargin mimicked thrombin actions on ET-1 mRNA induction. Thrombin-mediated activation of ET-1 mRNA was reduced by specific calmodulin antagonists W7 or calmidazolium and after inhibition of CaM kinase II by KN-62. Inhibition of calcium/calmodulin-dependent phosphatase calcineurin by cyclosporin A, however, stimulated ET-1 mRNA in human endothelial cells. Phosphotyrosine immunoblot assays show that calcium/calmodulin-dependent signaling pathways precede thrombin-induced tyrosine phosphorylation, and that the calcium/calmodulin-dependent phosphatase calcineurin also exerts its effects via activation of protein tyrosine kinases. These observations demonstrate that thrombin stimulates the preproET-1 gene in human endothelial cells through calcium-dependent activation of CaM kinase and protein tyrosine kinases, and that calcineurin may also participate in regulation of the prepro ET-1 gene.
J Cardiovasc Pharmacol 1995
PMID:Thrombin-mediated ET-1 gene regulation involves CaM kinases and calcineurin in human endothelial cells. 858 30

Phospholamban (PLB) plays a primary role in regulating cardiac sarcoplasmic reticulum (SR) Ca(2+)-ATPase activity. Dephosphorylated PLB suppresses the SR Ca(2+) pump activity, whereas phosphorylation of PLB leads to deinhibition. A widely accepted sequential model of dual site PLB phosphorylation states that PKA-dependent phosphorylation of Ser(16) is obligatory to phosphorylation of Thr(17) by Ca(2+)/calmodulin-dependent kinase II, and mainly accounts for beta-adrenergic receptor mediated cardiac relaxation. However, emerging evidence supports independent phosphorylation of Ser(16) and Thr(17) and their independent contributions to cardiac relaxation. Furthermore, concurrent activation of PKA and CaMKII signaling pathways exhibits a robust synergistic effect on phosphorylation of Thr(17), but not of Ser(16). Thus, the synergistic interaction may masquerade as a sequential phosphorylation of Ser(16) and Thr(17) under certain circumstances. Further studies are required to determine the exact process of dual site PLB phosphorylation and its functional roles in healthy and diseased hearts.
Trends Cardiovasc Med 2002 Feb
PMID:Dual site phospholamban phosphorylation and its physiological relevance in the heart. 1185 50

The aim of this study was to investigate possible regulation of the hyperpolarization-activated current (I(f)) by cytosolic calcium in guinea-pig sino-atrial (SA) node cells. Isolated SA node cells were superfused with physiological saline solution (36 degrees C) and the perforated patch voltage-clamp technique used to record I(f) activated by hyperpolarizing voltage steps. A 10-min loading of SA node cells with the calcium chelator BAPTA (using 10 microM BAPTA-AM) significantly reduced the amplitude of I(f) at all potentials studied (69+/-8% at -80 mV, n=6). BAPTA loading also shifted the voltage of half-activation (V(h)) of the conductance from -83+/-2 mV in control to -93+/-2 mV in BAPTA (n=6) without significantly altering the slope of activation. The calmodulin antagonists W-7 (10 microM), calmidazolium (25 microM) and ophiobolin A (20 microM) caused similar reductions in I(f) amplitude (73+/-4, 86+/-9 and 59+/-6% at -80 mV, n=6, 5 and 4, respectively) and shifts in V(h) (11+/-3, 14+/-3 and 8+/-2 mV). In cells pre-treated with W-7, exposure to BAPTA caused no further reduction in current amplitude (n=6). I(f) current amplitude was unaffected by the calmodulin dependent kinase (CaMKII) inhibitor KN-93 (1 microM) although this CaMKII inhibition did reduce L-type calcium by 48+/-19% at 0 mV (n=3). These results are consistent with a role for calcium and calmodulin in the regulation of I(f), via a mechanism that is independent of CaMKII. Alterations in intracellular calcium during the cardiac cycle may be involved in fine tuning the voltage-dependent properties of I(f) and may thus determine its relative contribution to pacemaking in the SA node.
Cardiovasc Res 2003 Feb
PMID:Modulation of the hyperpolarization-activated current (I(f)) by calcium and calmodulin in the guinea-pig sino-atrial node. 1256 22

Ca2+/calmodulin-dependent protein kinase II (CaMKII), a critical transducer of Ca2+ signaling, is a multifunctional protein kinase which can phosphorylate a wide range of substrates and regulate numerous cellular functions. The delta isoforms of CaMKII predominate in the heart and two splice variants of CaMKIIdelta, deltaB and deltaC, have been demonstrated to be present in the adult mammalian myocardium. The deltaB isoform contains a nuclear localization signal (NLS) that is absent from deltaC, and consequently, the two isoforms have different subcellular localization. Recent work from our laboratory and others has implicated CaMKII in the development of cardiac hypertrophy and heart failure. The specific roles of these CaMKII isoforms in regulating cardiac function appear to be determined by their subcellular localization. The nuclear deltaB isoform plays a key role in hypertrophic gene expression, whereas the cytoplasmic deltaC isoform can affect excitation-contraction (E-C) coupling through phosphorylation of Ca2+ regulatory proteins and may also transduce signals leading to apoptosis. In addition, the nuclear deltaB and the cytoplasmic deltaC isoforms of CaMKII are differentially regulated in pressure overload-induced cardiac hypertrophy. This review focuses on evidence that CaMKII plays an essential role in transcriptional activation associated with cardiac hypertrophy, as well as the aberrant Ca2+ handling and apoptosis that may contribute to heart failure. The hypothesis that CaMKII isoform selective activation, localization and substrate phosphorylation lead to specificity in the resultant signaling pathways is discussed.
Cardiovasc Res 2004 Aug 15
PMID:Role of Ca2+/calmodulin-dependent protein kinase II in cardiac hypertrophy and heart failure. 1527 73

Cardiac hypertrophy occurs in as many as 47% of normotensive individuals who chronically use cocaine. We investigated the effects of cocaine, in concentrations commonly found in chronic cocaine users, on calcium/calmodulin kinase (CaMK), and whether cocaine can activate CaMK, increase cardiac myocyte protein expression, and cause cardiac hypertrophy in this manner. In series I to III, 0 (control) or cocaine in concentrations of 10 to 10 mol/L was added to cultured adult rat cardiac ventricular myocytes to determine by Western blots and by P incorporation the optimal treatment time and the optimal dose for CaMK activation. In series I, cocaine, 10 mol/L, increased myocyte CaMKII translocation from myocyte soluble to particulate fractions by > or =73 +/- 9% (P < 0.01) in comparison with controls but did not cause the translocation of CaMKI or CaMKIV. In series II and III, cocaine treatment of myocytes for 15 minutes increased maximal CaMKII activity by 86.5 +/- 13.3% (P < 0.001) and a cocaine dose of 5 x 10 mol/L increased CaMKII activity by 169.5 +/- 18.1% (P < 0.001). In series IV we measured by silver staining beta-myosin heavy chain protein (beta-MHC) expression in myocytes before and after cocaine and also CaMK inhibition with KN-62 (1-[N,O-bis-(5-isoquinolinesulfonyl)-N-methyl-L-tyrosyl]-4-phenylpiperazine). In these experiments, cocaine, 5x10 mol/L, increased myocyte protein concentration by 29.2 +/- 2.8%, and beta-MHC by 93.2 +/- 8.8% (P < 0.001). In series V and VI, cocaine effects on calcium currents (ICa) and intracellular Ca ([Ca]i) were determined before and after CaMK inhibition with KN-62 in rat myocytes. Cocaine, 10 mol/L, enhanced ICa peak amplitude in a voltage-dependent manner (by 173.9 +/- 14.9% at -20 mV and by 38.4 +/- 6.9% at 0 mV P < 0.01). Cocaine, 10 to 10 mol/L, in series VI promoted Ca transients from myocyte sarcoplasmic reticulum and increased [Ca]i to 607 +/- 141 x 10 mol/L (P < 0.05). KN-62 decreased cocaine-induced myocyte protein expression by 76.6%, and beta-MHC by 66.2% (P < 0.01) and significantly decreased cocaine-induced Ca transients and [Ca]i. We conclude that CaMKII activation is an important mechanism whereby cocaine can cause myocyte hypertrophy.
J Cardiovasc Pharmacol 2006 Jul
PMID:Cocaine activates calcium/calmodulin kinase II and causes cardiomyocyte hypertrophy. 1689 8

Because changes in intracellular Ca(2+) concentration are the final signals of electrical activity in excitable cells, many mechanisms have evolved to regulate Ca(2+) influx. Among the most important are those pathways that directly regulate the ion channels responsible for regulating and generating the Ca(2+) influx signal. Recent work has demonstrated that the Ca(2+) binding protein calmodulin (CaM) and the Ca(2+)/CaM-sensitive kinase CaMKII are important modulators of cardiac ion channels. Thus, Ca(2+) participates in feedback modulation to control electrical activity. This review highlights various mechanisms by which CaM and CaMKII regulate cardiovascular ion channel activity and presents a novel model for CaMKII regulation of Ca(V)1.2 Ca(2+) channel function.
Cardiovasc Res 2007 Mar 01
PMID:Calmodulin and CaMKII as molecular switches for cardiac ion channels. 1713 69

Calcium (Ca(2+)) is the central second messenger in the translation of electrical signals into mechanical activity of the heart. This highly coordinated process, termed excitation-contraction coupling or ECC, is based on Ca(2+)-induced Ca(2+) release from the sarcoplasmic reticulum (SR). In recent years it has become increasingly clear that several Ca(2+)-dependent proteins contribute to the fine tuning of ECC. One of these is the Ca(2+)/calmodulin-dependent protein kinase (CaMK) of which CaMKII is the predominant cardiac isoform. During ECC CaMKII phosphorylates several Ca(2+) handling proteins with multiple functional consequences. CaMKII may also be co-localized to distinct target proteins. CaMKII expression as well as activity are reported to be increased in heart failure and CaMKII overexpression can exert distinct and novel effects on ECC in the heart and in isolated myocytes of animals. In the present review we summarize important aspects of the role of CaMKII in ECC with an emphasis on recent novel findings.
Cardiovasc Res 2007 Mar 01
PMID:Role of Ca2+/calmodulin-dependent protein kinase (CaMK) in excitation-contraction coupling in the heart. 1715 85

Beta-adrenergic receptor activation plays an important role in the progression of human heart failure and the treatment of patients with beta-blockers has greatly improved the outcome of the disease. However, heart failure still is one of the leading causes of death in various countries and there is an imperative need for additional targets for the treatment of the disease. Recent studies by various groups have analyzed the downstream signaling pathways activated in response to beta-adrenergic stimulation that have the potential to become important targets for future treatments of heart failure. This review focuses on the significance of these pathways in the pathophysiology of heart failure in response to beta-adrenergic stimulation. More specifically the roles of PDE3, phosphorylation of phospholamban, and CaMKII activation are extensively discussed.
Expert Rev Cardiovasc Ther 2007 Jan
PMID:Beta-adrenergic pathways in human heart failure. 1718 63

In response to pathologic stresses such as hypertension or myocardial infarction, the heart undergoes a remodeling process that is characterized by myocyte hypertrophy, myocyte death and fibrosis, resulting in impaired cardiac function and heart failure. Cardiac remodeling is associated with derepression of genes that contribute to disease progression. This review focuses on evidence linking members of the Ca(2+)/calmodulin-dependent protein kinase (CaMK) superfamily, specifically CaMKII, protein kinase D (PKD) and microtubule associated kinase (MARK), to stress-induced derepression of pathological cardiac gene expression through their effects on class IIa histone deacetylases (HDACs).
Cardiovasc Res 2007 Mar 01
PMID:Derepression of pathological cardiac genes by members of the CaM kinase superfamily. 1721 38

Calcium/calmodulin-dependent kinase II (CaMKII) is a multifunctional serine/threonine kinase widely distributed in a number of tissue types. Activation of CaMKII has been linked to important downstream physiological processes, including apoptosis, hypertrophy, and arrhythmia in the heart. Pharmacological or genetic inhibition of CaMKII has been shown to improve health outcomes in a number of animal models. In this review, we summarize the structural and functional properties of CaMKII and detail its role in cardiac arrhythmia, structural heart disease, and sudden death.
J Cardiovasc Electrophysiol 2008 Dec
PMID:CaMKII and its role in cardiac arrhythmia. 1880 70


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