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)

Cortical glutamatergic and nigral dopaminergic afferents impinge on projection spiny neurons of the striatum, providing the most significant inputs to this structure. Isolated activation of glutamate or dopamine (DA) receptors produces short-term effects on striatal neurons, whereas the combined stimulation of both glutamate and DA receptors is able to induce long-lasting modifications of synaptic excitability. Repetitive stimulation of corticostriatal fibres causes a massive release of both glutamate and DA in the striatum and, depending on the glutamate receptor subtype preferentially activated, produces either long-term depression (LTD) or long-term potentiation (LTP) of excitatory synaptic transmission. D1-like and D2-like DA receptors interact synergistically to allow LTD formation, while they operate in opposition during the induction phase of LTP. Corticostriatal synaptic plasticity is severely impaired after chronic DA denervation and requires the stimulation of DARPP-32, a small protein expressed in dopaminoceptive spiny neurons which acts as a potent inhibitor of protein phosphatase-1. In addition, the formation of LTD and LTP requires the activation of PKG and PKA, respectively, in striatal projection neurons. These kinases appear to be stimulated by the activation of D1-like receptors in distinct neuronal populations.
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PMID:Dopaminergic control of synaptic plasticity in the dorsal striatum. 1128 3

Protein kinase A (PKA) can play a critical role in the modulation of neuronal excitability. We examined the role of PKA in the modulation of abnormal spontaneous activity (SA) originating from the chronically compressed dorsal root ganglion (CCD). The L(4) and L(5) dorsal root ganglia (DRGs) were compressed by inserting a stainless steel rod into each corresponding intervertebral foramen. After 1-14 postoperative days, SA in DRG neurons with myelinated axons was recorded in vitro from teased dorsal root microfilaments. Rp-cAMPS (5-500 microM), a specific inhibitor of PKA, caused a dose-dependent decrease in the discharge rate of SA when topically applied to the DRG. The highest dose completely blocked the SA, but not the conduction of action potentials. H89 (10 microM), another PKA inhibitor, also markedly decreased SA. Sp-cAMPS (500 microM), a specific activator of PKA, increased the discharge rate of SA in all injured units tested, but did not trigger firing in silent neurons. Okadaic acid (0.1 microM), a protein phosphatase inhibitor, and forskolin (1 microM), an adenyl cyclase activator, each significantly increased the discharge rate of SA. These results strongly suggest that PKA modulates the SA in injured DRG neurons with myelinated axons.
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PMID:Protein kinase A modulates spontaneous activity in chronically compressed dorsal root ganglion neurons in the rat. 1157 43

Mechanism of adrenergically activated calcium response in freshly isolated brown preadipocytes was studied with fluorescent probe Fura-2. Application of a direct activator of adenylylcyclase forskolin or cell permeable analog BrcAMP caused rise in the intracellular calcium level that was even higher than after the application of norepinephrine. Protein kinase A inhibitor H-89 in a dose-dependent manner reduced, while inhibitor of total phosphodiesterase activity IBMX, or protein phosphatase inhibitor ocadaic acid enhanced norepinephrine or isoproterenol initiated cellular calcium responses. It is concluded that cAMP and protein kinase A mediated phosphorylation play a crucial role in adrenergically initiated calcium signalling in brown preadipocytes.
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PMID:[Adenylyl cyclase pathway is involved in the regulation of intracellular calcium level regulation in brown preadipocytes]. 1186 63

Early studies identified two bona fide protein phosphatase 2A (PP2A)-encoding genes in Saccharomyces cerevisiae, designated PPH21 and PPH22. In addition, three PP2A-related phosphatases, encoded by PPH3, SIT4 and PPG1, have been identified. All share as much as 86% sequence similarity at the amino acid level. This review will focus primarily on Pph21 and Pph22, but some aspects of Sit4 regulation will also be discussed. Whereas a role for PP2A in yeast morphology and cell cycle has been readily recognized, uncovering its function in yeast signal transduction is a more recent breakthrough. Via their interaction with phosphorylated Tap42, PP2A and Sit4 play a pivotal role in target of rapamycin (TOR) signalling. PPH22 overexpression mimics overactive cAMP-PKA (protein kinase A) signalling and PP2A and Sit4 might represent ceramide signalling targets. The methylation of its catalytic subunit stabilizes the heterotrimeric form of PP2A and might counteract TOR signalling. We will show how these new elements could lead us to understand the role and regulation of PP2A in nutrient-induced signalling in baker's yeast.
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PMID:Protein phosphatase 2A on track for nutrient-induced signalling in yeast. 1192 36

The regulation of protein phosphatase (PP) activity by cardiac beta-adrenergic receptor stimulation with isoproterenol (ISO) was studied in four groups of guinea pigs consisting of seven animals each. Group 1 received the vehicle solution only intraperitoneally; group 2, 6 microg/kg of ISO; group 3, 60 microg/kg of ISO; and group 4, 600 microg/kg of ISO. Total PP activity (consisting of both type 1 and type 2A PP), activity of each PP subtype, the cAMP-dependent protein kinase activity ratio (-cAMP/+cAMP), the phosphorylation of PP inhibitor 1, and the phosphorylation of phospholamban were measured in ventricular tissue. PP activity was also studied in ventricular cardiomyocytes isolated from guinea pigs treated with and without 1 microM ISO or 1 microM ISO plus 10 microM propranolol, an antagonist of the beta-adrenoceptor. PP activity decreased significantly in membrane vesicles, but not in cytosolic fractions, of guinea pigs treated with 60 and 600 microg/kg of ISO compared with untreated animals. The PKA activity ratio, PLB phosphorylation, and PP inhibitor 1 phosphorylation increased in ventricles of guinea pigs treated with 60 and 600 microg/kg of ISO compared with vehicle-treated animals. The decrease in overall PP activity was due primarily to a reduction in type 1 but not type 2A PP activity. In isolated ventricular cardiomyocytes, PP activity was decreased significantly after treatment with 1 microM ISO, and this inhibition was reversed by treatment with 10 microM propranolol. The membrane vesicles of group 1 animals did not release any catalytic subunit of type 1 PP upon phosphorylation by exogenous PKA. These results indicate that activation of cardiac beta-adrenoceptors inhibits type 1 PP activity via phosphorylation of PP inhibitor 1 in the ventricles. This effect is associated with the well-known effect of ISO on increases in the PKA activity ratio and PLB phosphorylation. Inhibition of type 1 PP activity could be one possible mechanism, in addition to activation of adenylate cyclase, by which ISO mediates enhanced contractility of the heart.
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PMID:Inhibition of type 1 protein phosphatase activity by activation of beta-adrenoceptors in ventricular myocardium. 1193 39

Earlier we demonstrated that activation of a ceramide-activated protein phosphatase (CAPP) conferred normal growth and secretion to yeast lacking their complement of exocytic v-SNAREs (Snc1,2) or bearing a temperature-sensitive mutation in an exocytic t-SNARE (Sso2). CAPP activation led to Sso dephosphorylation and enhanced the assembly of t-SNAREs into functional complexes. Thus, exocytosis in yeast is modulated by t-SNARE phosphorylation. Here, we show that endocytic defects in cells lacking the v- and t-SNAREs involved in endocytosis are also rescued by CAPP activation. Yeast lacking the Tlg1 or Tlg2 t-SNAREs, the Snc v-SNAREs, or both, undergo endocytosis after phosphatase activation. CAPP activation correlated with restored uptake of FM4-64 to the vacuole, the uptake and degradation of the Ste2 receptor after mating factor treatment, and the dephosphorylation and assembly of Tlg1,2 into SNARE complexes. Activation of the phosphatase by treatment with C(2)-ceramide, VBM/ELO gene inactivation, or by the overexpression of SIT4 was sufficient to confer rescue. Finally, we found that mutation of single PKA sites in Tlg1 (Ser31 to Ala31) or Tlg2 (Ser90 to Ala90) was sufficient to restore endocytosis, but not exocytosis, to snc cells. These results suggest that endocytosis is also modulated by t-SNARE phosphorylation in vivo.
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PMID:t-SNARE phosphorylation regulates endocytosis in yeast. 1200 55

It is believed that brief, high amplitude Ca2+ transients, as found in fast-twitch muscles, are not sufficient to activate the calcineurin (Cn)-dependent signaling pathway involved in regulation of slow myosin and slow sarcoplasmic reticulum Ca2+-ATPase genes (Olson and Williams, Cell 101: 689-692, 2000). The results reported here try to fill the gap between this molecular knowledge, and the still fragmentary pieces of information on a possible different role of calcineurin in the same type of muscles. In the present work calcineurin was determined immunocytochemically by labeling fast- and slow-twitch fibers of representative rabbit muscles with anti-CnB antibodies, and was assessed by western blotting of isolated subcellular fractions. Calcineurin was found to be largely soluble and to be constitutively overexpressed in fast muscle as CnAalpha and CnAbeta isoforms, the latter appearing to be predominant. Particulate calcineurin was not only associated with myofibrils but also with membranes of various origins. Fluorescence microscopy showed that calcineurin was distributed in the same pattern with respect to sarcomeres in both types of fibers, and formed punctate dots spanning the I-Z-I region, rather than being exclusively located at the Z-line, a disposition described for cardiomyocytes (Frey et al., Proc Natl Acad Sci USA 97: 14,632-14,637, 2000). From knowledge that, in mammalian skeletal muscle fibers, junctional triads are located at the A-I band boundary, we explored the distribution of calcineurin between triadic components, after having verified that it was present in very low amounts in dystrophin-enriched sarcolemmal membranes. Our results demonstrate that a small but significant proportion of calcineurin coenriched with transverse tubules (TT), and copurified with the DHPR and with DHPR-associated PKA-AKAP15/18, thus suggesting that it is assembled as a multiprotein complex in the junctional membrane domain of TT. The membrane specificity of this association is further corroborated by the negative evidence for the presence of calcineurin in SR terminal cisternae. Calcineurin was separated from the DHPR and isolated as a AKAP15/18 subcomplex, including beta2 adrenergic receptor, in addition to PKA and calcineurin, following equilibrium centrifugation of detergent extracts on a linear sucrose gradient. We show that the alpha1 subunit skeletal isoform of the DHPR, is a substrate for calcineurin dephosphorylation, after previous phosphorylation by endogenous PKA.
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PMID:Clues to calcineurin function in mammalian fast-twitch muscle. 1203 88

Rhythmic low and high frequency activity in thalamocortical networks depend critically on activation of low- and high-voltage-activated (LVA, HVA) Ca2+ currents. In order to test whether Ca2+ currents are modified during repetitive activation, acutely isolated thalamocortical relay neurons of rats, at postnatal days 12 (P12) to P20, were investigated using patch-clamp, Ca2+ imaging and Western blot techniques. High-voltage-activated, but not LVA Ca2+ currents were reduced significantly during 2 Hz stimulation. Ca2+ imaging experiments demonstrated a close correlation between the increase in intracellular Ca2+ levels and the decrease in HVA Ca2+ current amplitudes. Further examination of HVA Ca2+ currents revealed a 'U-shaped' inactivation curve and a time-dependent inactivation process that could be described by a two-exponential function. The 'U-shape' was significantly reduced, current amplitude was increased significantly and time-dependent inactivation revealed a one-exponential decline with Ba2+ as the charge carrier, following activation of the cAMP/PKA pathway, and following application of phosphatase inhibitors (ascomycin, calyculin A). Western blot analysis and the effect of ascomycin indicated an involvement of calcineurin in the inactivation process. Isolation of HVA Ca2+ current components by subtype-specific blockers revealed that changes in time-dependent inactivation, inactivation curve and current amplitude were carried mainly by L-type and N-type Ca2+ currents. Furthermore, Ca2+-dependent inactivation was operative during stimulation protocols mimicking tonic action potential firing. These data indicate a modulation of L- and N-type Ca2+ channels by phosphorylation, resulting jointly in an increased intracellular Ca2+ influx during activity of the ascending brainstem system, the latter occurring during states of wakefulness.
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PMID:Modulation of Ca2+ currents in rat thalamocortical relay neurons by activity and phosphorylation. 1205 68

Neurotensin modulates dopaminergic transmission in the nigrostriatal system. DARPP-32, a dopamine- and cAMP-regulated phosphoprotein of Mr 32 kDa, is phosphorylated on Thr34 by cAMP-dependent protein kinase, resulting in its conversion into a potent inhibitor of protein phosphatase-1 (PP 1). Here, we examined the effect of neurotensin on DARPP-32 Thr34 phosphorylation using mouse neostriatal slices. Neurotensin stimulated DARPP-32 Thr34 phosphorylation by 4-7-fold with a K(0.5) of approximately 50 nM. The effect of neurotensin was antagonized by a combined neurotensin receptor type-1 (NTR1)/type-2 (NTR2) antagonist, SR142948. It was not antagonized by a NTR1 antagonist, SR48692 or by a NTR2 antagonist, levocabastine; neither was it antagonized by the two combined. Pretreatment with TTX or cobalt abolished the effect of neurotensin. The effect of neurotensin was antagonized by a dopamine D1 antagonist, SCH23390, and by ionotropic glutamate receptor antagonists, MK801 and CNQX. These results indicate that neurotensin stimulates the release of dopamine from nigrostriatal presynaptic terminals in an NMDA receptor- and AMPA receptor-dependent manner, leading to the increase in DARPP-32 Thr34 phosphorylation. Neurotensin stimulated the phosphorylation of Ser845 of the AMPA receptor GluR1 subunit in wild-type mice but not in DARPP-32 knockout mice. Thus, neurotensin, by stimulating the release of dopamine, activates the dopamine D1-receptor/cAMP/PKA/DARPP-32/PP 1 cascade.
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PMID:Neurotensin regulates DARPP-32 thr34 phosphorylation in neostriatal neurons by activation of dopamine D1-type receptors. 1206 80

The eel intestinal epithelium responds to an acute hypertonic challenge by a biphasic increase of the rate of Cl(-) absorption (measured as short circuit current, Isc, and creating a negative transepithelial potential, V(te), at the basolateral side of the epithelium). While the first, transient phase is bumetanide-insensitive, the second, sustained phase is bumetanide-sensitive, reflecting activation of the apically located Na(+)-K(+)-2Cl(-) (NKCC) cotransporter, which correlates with the cellular RVI response. Here, we investigated the involvement of the cytoskeleton and of serine/threonine phosphorylation events in the osmotic stress-induced ion transport in the eel intestinal epithelium, focusing on the sustained RVI phase, as well as on the previously uncharacterized response to hypotonic stress. The study was carried out using confocal laser scanning microscopy, a quantitative F-actin assay, and transepithelial electrophysiological measurements (V(te) and Isc) in Ussing chambers. Hypertonic stress did not detectably alter either net F-actin content or F-actin organization. In contrast, a brief exposure to hypotonic stress decreased the total cellular F-actin content in eel intestinal epithelium by about 15%, detectable morphologically mainly as a decrease in the intensity of the apical brush border F-actin labeling.The bumetanide-sensitive response of V(te) and Isc to hypertonicity was potently inhibited by treatment with either cytochalasin, latrunculin A, colchicine, the protein kinase C (PKC) inhibitor chelerythrine, the myosin light chain kinase (MLCK) inhibitor ML-7, or the serine/threonine protein phosphatase inhibitor Calyculin A, but was unaffected by the PKA inhibitor H-89. The electrophysiological response of the epithelium to hypotonic stress was characterized by a sustained decrease of V(te) and Isc, which was smaller and recovered faster in the presence of either cytochalasin, latrunculin A, or colchicine. It is concluded that in eel intestinal epithelium, the changes in ion transport in response to both hyper- and hypotonic stress require the integrity of both F-actin and microtubules. In addition, the shrinkage-induced activation of NKCC appears to require the activity of both PKC and MLCK. It is suggested that NKCC regulation by hypertonic stress involves an interaction between the cytoskeleton and protein phosphorylation events.
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PMID:Roles of the cytoskeleton and of protein phosphorylation events in the osmotic stress response in eel intestinal epithelium. 1229 22


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