Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:3.1.3.16 (calcineurin)
17,112 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Ca(2+)/calmodulin-dependent protein kinase phosphatase (CaMKP) and its nuclear isoform CaMKP-N are unique Ser/Thr protein phosphatases that negatively regulate the Ca(2+)/calmodulin-dependent protein kinase (CaMK) cascade by dephosphorylating multifunctional CaMKI, II, and IV. However, the lack of specific inhibitors of these phosphatases has hampered studies on these enzymes in vivo. In an attempt to obtain specific inhibitors, we searched inhibitory compounds and found that Evans Blue and Chicago Sky Blue 6B served as effective inhibitors for CaMKP. These compounds also inhibited CaMKP-N, but inhibited neither protein phosphatase 2C, another member of PPM family phosphatase, nor calcineurin, a typical PPP family phosphatase. The minimum structure required for the inhibition was 1-amino-8-naphthol-4-sulfonic acid. When Neuro2a cells cotransfected with CaMKIV and CaMKP-N were treated with these compounds, the dephosphorylation of CaMKIV was strongly suppressed, suggesting that these compounds could be used as potent inhibitors of CaMKP and CaMKP-N in vivo as well as in vitro.
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PMID:Inhibitors of the Ca(2+)/calmodulin-dependent protein kinase phosphatase family (CaMKP and CaMKP-N). 1789 24

Ca2+ signalling plays an important role in excitation-contraction coupling and the resultant force output of skeletal muscle. It is also known to play a crucial role in modulating both short- and long-term muscle cellular phenotypic adaptations associated with these events. Ca2+ signalling via the Ca2+/calmodulin (CaM)-dependent phosphatase calcineurin (CnA) and via Ca2+/CaM-dependent kinases, such as CaMKI and CaMKII, is known to regulate hypertrophic growth in response to overload, to direct slow versus fast fibre gene expression, and to contribute to mitochondrial biogenesis. The CnA- and CaMK-dependent regulation of the downstream transcription factors nuclear factor of activated T cells (NFAT) and myocyte-specific enhancer factor 2 are known to activate muscle-specific genes associated with a slower, more oxidative fibre phenotype. We have also recently shown the expression of utrophin A, a cytoskeletal protein that accumulates at the neuromuscular junction and plays a role in maturation of the postsynaptic apparatus, to be regulated by CnA-NFAT and Ca2+/CaM signalling. This regulation is fibre-type specific and potentiated by interactions with the transcriptional regulators and coactivators GA binding protein (also known as nuclear respiratory factor 2) and peroxisome proliferator-activated receptor-gamma coactivator 1 alpha. Another downstream target of CnA signalling may be myostatin, a transforming growth factor-beta family member that is a negative regulator of muscle growth. While the list of the downstream targets of CnA/NFAT- and Ca2+/CaM-dependent signalling is emerging, the precise interaction of these pathways with the Ca2+-independent pathways p38 mitogen-activated protein kinase, extracellular signal-regulated kinases 1 and 2, phosphoinositide-3 kinase, and protein kinase B (Akt/PKB) must also be considered when deciphering fibre responses and plasticity to altered contractile load.
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PMID:Ca2+/calmodulin-based signalling in the regulation of the muscle fibre phenotype and its therapeutic potential via modulation of utrophin A and myostatin expression. 1805 17

Neurabin is a scaffolding protein that interacts with actin and protein phosphatase-1. Highly enriched in the dendritic spine, neurabin is important for spine morphogenesis and synaptic formation. However, less is known about the role of neurabin in hippocampal plasticity and its possible effect on behavioral functions. Using neurabin knockout (KO) mice, here we studied the function of neurabin in hippocampal synaptic transmission, plasticity and behavioral memory. We demonstrated that neurabin KO mice showed a deficit in contextual fear memory but not auditory fear memory. Whole-cell patch clamp recordings in the hippocampal CA1 neurons showed that long-term potentiation (LTP) was significantly reduced, whereas long-term depression (LTD) was unaltered in neurabin KO mice. Moreover, increased AMPA receptor but not NMDA receptor-mediated synaptic transmission was found in neurabin KO mice, and is accompanied by decreased phosphorylation of GluR1 at the PKA site (Ser845) but no change at the CaMKII/PKC site (Ser831). Pre-conditioning with LTD induction rescued the following LTP in neurabin KO mice, suggesting the loss of LTP may be due to the saturated synaptic transmission. Our results indicate that neurabin regulates contextual fear memory and LTP in hippocampal CA1 pyramidal neurons.
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PMID:Neurabin contributes to hippocampal long-term potentiation and contextual fear memory. 1818 88

Synaptic plasticity has been studied extensively at excitatory synapses, whereas studies on plasticity at GABAergic inhibitory synapses have been limited. In the rat cerebellar cortex, postsynaptic depolarization of a Purkinje neuron (PN) induces long-term potentiation of GABA(A) receptor (GABA(A)R) responsiveness (termed rebound potentiation; RP). Induction of RP requires an increase in intracellular Ca(2+) concentration and resultant activation of Ca(2+)/calmodulin-dependent protein kinase II (CaMKII). We previously reported that GABA(B) receptor (GABA(B)R) activation coupled with depolarization suppresses RP induction by facilitating protein phosphatase 1 (PP-1)-mediated inhibition of CaMKII through down-regulation of cAMP-dependent protein kinase A (PKA) activity. Here, we examined the involvement of metabotropic glutamate receptor type 1 (mGluR1) in RP regulation. RP was monitored with the amplitudes of either the current responses to GABA or miniature inhibitory postsynaptic currents recorded from a PN in a primary culture or in a cerebellar slice. Inhibition of mGluR1 by an antagonist, 7(hydroxyimino)cyclopropa[b]chromen-1a-carboxylate-ethyl-ester (CPCCOEt), prevented RP induction, which was abolished either by activation of adenylyl cyclase or by inhibition of PP-1. Furthermore, mGluR1 inhibition impaired depolarization-induced CaMKII activation. By contrast, activation of mGluR1 by the agonist (R,S)3,5-dihydroxyphenylglycine (DHPG) rescued RP induction from its suppression by GABA(B)R activation. The rescue was impaired either by inhibition of PKA or by facilitation of PP-1 activity. In addition, mGluR1 activation counteracted the GABA(B)R-mediated CaMKII inhibition. Taken together, these results suggest that mGluR1 activity counteracts GABA(B)R activity and contributes to RP induction through PKA activation, down-regulation of PP-1 and up-regulation of CaMKII.
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PMID:mGluR1-mediated facilitation of long-term potentiation at inhibitory synapses on a cerebellar Purkinje neuron. 1827 62

Cardiac hypertrophy is promoted by adrenergic overactivation and can progress to heart failure, a leading cause of mortality worldwide. Although cAMP is among the most well-known signaling molecules produced by beta-adrenergic receptor stimulation, its mechanism of action in cardiac hypertrophy is not fully understood. The identification of Epac (exchange protein directly activated by cAMP) proteins as novel sensors for cAMP has broken the dogma surrounding cAMP and protein kinase A. However, their role and regulation in the mature heart remain to be defined. Here, we show that cardiac hypertrophy induced by thoracic aortic constriction increases Epac1 expression in rat myocardium. Adult ventricular myocytes isolated from banded animals display an exaggerated cellular growth in response to Epac activation. At the molecular level, Epac1 hypertrophic effects are independent of its classic effector, Rap1, but rather involve the small GTPase Ras, the phosphatase calcineurin, and Ca(2+)/calmodulin-dependent protein kinase II. Importantly, we find that in response to beta-adrenergic receptor stimulation, Epac1 activates Ras and induces adult cardiomyocyte hypertrophy in a cAMP-dependent but protein kinase A-independent manner. Knockdown of Epac1 strongly reduces beta-adrenergic receptor-induced hypertrophic program. Finally, we report for the first time that Epac1 is mainly expressed in human heart as compared with Epac2 isoform and is increased in heart failure. Taken together, our data demonstrate that the guanine nucleotide exchange factor Epac1 contributes to the hypertrophic effect of beta-adrenergic receptor in a protein kinase A-independent fashion and may, therefore, represent a novel therapeutic target for the treatment of cardiac disorders.
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PMID:Epac mediates beta-adrenergic receptor-induced cardiomyocyte hypertrophy. 1832 24

We previously reported behavioral and electrophysiological evidence indicating that superior cervical ganglia (SCG) from rats that developed hypertension as a result of chronic psychosocial stress expressed ganglionic long-term potentiation (gLTP) in vivo. In the present study, we present additional supportive evidence by measuring changes in protein levels of essential signaling molecules in ganglia from chronically stressed rats. We compared protein levels of essential, LTP-related signaling molecules in ganglia isolated from chronic stress-hypertensive rats, known to have expressed gLTP, with those of the same molecules in normal ganglia 1h after eliciting gLTP by high frequency stimulation (HFS) in vitro. Immunoblot analysis showed a significant increase in the levels of phosphorylated CaMKII, total CaMKII, nitric oxide synthase (NOS-1), and calmodulin in SCG from both chronically stressed rats and from normal rat ganglia in which gLTP was expressed by HFS in vitro. Additionally, there was a parallel reduction in calcineurin protein levels in ganglia from both groups. The present results confirm that ganglia from stressed rats have expressed gLTP in vivo and that synaptic plasticity in sympathetic ganglia may involve a molecular cascade largely similar to that of LTP in the hippocampal CA1 region.
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PMID:Expression of gLTP in sympathetic ganglia from stress-hypertensive rats: molecular evidence. 1838 86

Long-term potentiation in sympathetic ganglia (gLTP) is similar to LTP of the hippocampal area CA1 in that its expression involves similar changes in signaling molecules. We have shown previously that the stress-prone, hypertensive obese Zucker rats (OZR) expressed gLTP in sympathetic ganglia and that high blood pressure was reduced by treatment with 5-HT(3) receptor antagonists. In the present study, we present additional electrophysiological evidence for the pre-expression of gLTP in sympathetic ganglia from OZR indicated by failure of repetitive stimulation to express gLTP in isolated superior cervical ganglia (SCG) and inhibition of baseline ganglionic transmission by a 5-HT(3) receptor antagonist. We have also investigated the role of key signaling molecules in the expression of gLTP in the hypertensive OZR. Immunoblot analysis showed a significant increase in the levels of phosphorylated (P-)CaMKII and protein kinase C gamma (PKCgamma) in SCG from OZR. The ratio of P-CaMKII to the total CaMKII was markedly increased in OZR ganglia, suggesting increased phosphorylation of this molecule. Additionally, there was a significant decrease in the levels of calcineurin in ganglia. Furthermore, the neural nitric oxide synthase and hemeoxygenase II, which are essential for the expression of gLTP, were significantly elevated in OZR ganglia. The present findings confirm that ganglia from OZR have expressed gLTP and that synaptic plasticity in sympathetic ganglia may involve a molecular cascade similar to that of LTP of the brain hippocampal area CA1.
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PMID:Expression of gLTP in sympathetic ganglia of obese Zucker rats in vivo: molecular evidence. 1856 1

We have shown recently that either hypothyroidism or chronic psychosocial stress enhances the expression of LTD, which is reversed by chronic nicotine treatment. In this study, we investigated the effect of combining chronic psychosocial stress with hypothyroidism on LTD. We have also investigated the levels of signaling molecules important for LTD in hypothyroid, stressed-hypothyroid and nicotine-treated hypothyroid rats. Following paired pulse stimulation, LTD was evoked in the CA1 region of anesthetized rats. Combining chronic psychosocial stress with hypothyroidism does not further enhance LTD magnitude compared to either alone. Western blot analysis conducted 1 h after induction of LTD, showed that the levels of calcineurin and P-CaMKII were increased in hypothyroid and stressed-hypothyroid groups compared to that of the control group. However, the levels of calcineurin and P-CaMKII after paired pulsed stimulation were not further increased in stressed-hypothyroid group compared to the hypothyroid only group. In addition, these levels were normalized by chronic nicotine treatment. No change was detected in any of the groups in the levels of calmodulin, PKCgamma, and BDNF after paired pulse stimulation. Our results indicate that changes in the levels of calcineurin and P-CaMKII during expression of LTD in the CA1 region may explain the enhanced magnitude of LTD in hypothyroid rats, and its reversal by chronic nicotine treatment.
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PMID:Effect of chronic stress or nicotine on hypothyroidism-induced enhancement of LTD: electrophysiological and molecular studies. 1863 53

Sustained increase in central sympathetic outflow to ganglia may provide the repeated high frequency presynaptic activity required for induction of long-term potentiation in sympathetic ganglia (gLTP), which is known to be involved in the manifestation of a neurogenic form of hypertension, namely stress-hypertension. Aging is often viewed as a progressive decline in physiological competence with a corresponding impaired ability to adapt to stressful stimuli. Old animals have exaggerated sympathetic activity as well as increased morbidity and mortality during prolonged exposure to stressful stimuli. Using the superior cervical ganglion (SCG) as a model for sympathetic ganglia, electrophysiological and biochemical evidence show that mildly hypertensive aged rats (22-month old) have expressed gLTP in vivo. This is suggested by a number of lines of evidence. Firstly, a shift in input/output (I/O) curve of ganglia from aged rats to the left side of I/O curve of ganglia from 6-month old (adult) rats indicating expression of gLTP. Secondly, failure of in vitro high frequency stimulation to induce gLTP in ganglia isolated from aged rats, which indicates occlusion due to saturation, which, in turn, suggests in vivo expression of gLTP in these ganglia. Thirdly, in vitro inhibition of basal ganglionic transmission by blockers of gLTP (5-HT(3) antagonists) is observed in ganglia isolated from aged rats, but not in those from adult rats. Finally, immunoblot analysis revealed that protein levels of signaling molecules such as calcium-calmodulin kinase II (CaMKII; phosphorylated and total), which normally increase during expression of LTP, are elevated in ganglia isolated from aged rats compared to those from adult ones. Protein levels of calcineurin, which dephosphorylates P-CaMKII, were reduced in ganglia isolated from aged rats, probably as a support mechanism to allow prolonged phosphorylation of CaMKII. Our findings suggest in vivo expression of gLTP in sympathetic ganglia of aged animals, which may contribute to the moderate hypertension often seen in aged subjects.
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PMID:In vivo expression of ganglionic long-term potentiation in superior cervical ganglia from hypertensive aged rats. 1864 73

Calmodulin (CaM) mediates Ca-dependent regulation of numerous pathways in the heart, including CaM-dependent kinase (CaMKII) and calcineurin (CaN), yet the local Ca(2+) signals responsible for their selective activation are unclear. To assess when and where CaM, CaMKII, and CaN may be activated in the cardiac myocyte, we integrated new mechanistic computational models of CaM, CaMKII, and CaN with the Shannon-Bers model of excitation-contraction coupling in the rabbit ventricular myocyte. These models are validated with independent in vitro data. In the intact myocyte, model simulations predict that CaM is highly activated in the dyadic cleft during each beat, but not appreciably in the cytosol. CaMKII-delta(C) was almost insensitive to cytosolic Ca due to relatively low CaM affinity. Dyadic cleft CaMKII exhibits dynamic frequency-dependent responses to Ca, yet autophosphorylates only when local phosphatases are suppressed. In contrast, dyadic cleft CaN in beating myocytes is predicted to be constitutively active, whereas the extremely high affinity of CaN for CaM allows gradual integration of small cytosolic CaM signals. Reversing CaM affinities for CaMKII and CaN also reverses their characteristic local responses. Deactivation of both CaMKII and CaN seems dominated by Ca dissociation from the complex (versus Ca-CaM dissociation from the target). In summary, the different affinities of CaM for CaMKII and CaN determine their sensitivity to local Ca signals in cardiac myocytes.
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PMID:Calmodulin mediates differential sensitivity of CaMKII and calcineurin to local Ca2+ in cardiac myocytes. 1868 54


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