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)

InsP(3) binding to type-1, but not type-3, InsP(3) receptors is inhibited by calmodulin in a Ca(2+)-independent fashion [Cardy and Taylor (1998) Biochem. J. 334, 447-455], and Ca(2+) mobilization by type-1 InsP(3) receptors of cerebellum is inhibited by calmodulin [Patel, Morris, Adkins, O'Beirne and Taylor (1997) Proc. Natl. Acad. Sci. U.S.A. 94, 11627-11632]. Using cell types expressing predominantly type-1, -2 or -3 InsP(3) receptors, we show that InsP(3)-evoked Ca(2+) mobilization from each is similarly inhibited by calmodulin. In SH-SY5Y cells, which express largely type-1 receptors, calmodulin (IC(50) approximately 15 microM) inhibited InsP(3)-evoked Ca(2+) release only in the presence of Ca(2+). The inhibition was unaffected by calcineurin inhibitors. The effect of calmodulin did not result from enhanced metabolism of InsP(3) because calmodulin also decreased the sensitivity of the Ca(2+) stores to adenophostin A, a non-metabolizable InsP(3)-receptor agonist. Protein kinase A-catalysed phosphorylation of type-1 InsP(3) receptors was unaffected by Ca(2+)-calmodulin. Using a scintillation proximity assay to measure (125)I-calmodulin binding to glutathione S-transferase-fusion proteins, we identified two regions of the type-1 InsP(3) receptor (cyt1, residues -6 to 159; and cyt11, residues 1499-1649) that bound (125)I-calmodulin. The higher-affinity site (cyt11) was also photoaffinity labelled with N-hydroxysuccinimidyl-4-azidobenzoate (HSAB)-calmodulin. We speculate that Ca(2+)-independent binding of calmodulin to a site within the first 159 residues of the type-1 InsP(3) receptor inhibits InsP(3) binding and may thereby regulate the kinetics of Ca(2+) release. Ca(2+)-dependent inhibition of Ca(2+) release by calmodulin is mediated by a different site: it may reside on an accessory protein that associates with all three receptor subtypes, or Ca(2+)-calmodulin binding to a site lying between residues 1499 and 1649 of the type-1 receptor may inhibit Ca(2+) release from any tetrameric receptor that includes a type-1 subunit.
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PMID:Ca2+-calmodulin inhibits Ca2+ release mediated by type-1, -2 and -3 inositol trisphosphate receptors. 1062 May 13

(1) In homogenates of vitellogenic follicles from Hyalophora cecropia, cyclic nucleotides promoted the transfer of label from [gamma32P]-ATP to at least four polypeptides. PKI (6-20) amide, an inhibitor of PKA (cAMP-dependent protein kinase), prevented all four reactions. Quantitative tests using kemptide as a substrate indicated that 80% of the total follicular PKA activity was localized in the follicle cells; labeling at 45, 32, and 27 kDa was particle-associated and also restricted to the follicle cells, while a 58 kDa substrate was labeled only in homogenates of the oocyte. (2) When intact follicles were incubated in [32P]-phosphate and okadaic acid, a protein phosphatase inhibitor, the 32 kDa substrate again exhibited cAMP-dependent labeling. There was thus a physiological relationship between PKA activation and 32 kDa protein phosphorylation, while exposure of at least two of the other three substrates to appropriate kinases required homogenization. The latter was illustrated by phosphorylation of the 42 kDa small subunit of vitellogenin, which occurred only when homogenization mixed the proteins of the yolk bodies with cytoplasmic kinases. (3) PKA activation is known to promote the termination of vitellogenesis, even in the absence of detectable labeling of the 32 kDa substrate. The possibility remains that phosphorylation at 32 kDa concerns later aspects of postvellogenic development that were not tested by the assay system used here.
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PMID:Cyclic nucleotide-dependent protein phosphorylation in vitellogenic follicles of Hyalophora cecropia. 1064 68

In human normal thyrocytes, the cAMP-responsive signaling pathway plays a central role in gene regulation, cell proliferation, and differentiation. Constitutive activation of the cAMP signal transduction system has been documented in thyroid autonomously hyperfunctioning adenomas in which activating mutations in either the TSH receptor gene or the Gsalpha protein gene (gsp oncogene) have been described. The molecular mechanism whereby cAMP induces thyrocyte proliferation is unknown, but recent evidence suggests that the transcription factor cAMP response element binding protein (CREB) may serve as an important biochemical intermediate in this proliferative response. Herein we have investigated the expression of CREB in normal and tumoral thyroid tissues from a series of ten unrelated patients with autonomously hyperfunctioning adenomas, previously screened for mutations in the TSH receptor and Gsalpha genes. In all tumors examined, the expression of the activated, phosphorylated form of CREB was markedly reduced compared with that of the corresponding paired normal thyroid tissue, and this reduction was independent of the presence of mutations in the TSH receptor gene and Gsalpha gene. Moreover, no correlation was observed in these tissues between CREB phosphorylation and either protein kinase A activity or protein phosphatase expression. Thus, these data suggest that in human hyperfunctioning thyroid adenomas, the PKA/CREB system does not play a role in cell proliferation.
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PMID:The 3',5'-cyclic adenosine monophosphate response element binding protein (CREB) is functionally reduced in human toxic thyroid adenomas. 1065 Sep 54

Dopamine is a critical determinant of neostriatal function, but its impact on intrastriatal GABAergic signaling is poorly understood. The role of D(1) dopamine receptors in the regulation of postsynaptic GABA(A) receptors was characterized using whole cell voltage-clamp recordings in acutely isolated, rat neostriatal medium spiny neurons. Exogenous application of GABA evoked a rapidly desensitizing current that was blocked by bicuculline. Application of the D(1) dopamine receptor agonist SKF 81297 reduced GABA-evoked currents in most medium spiny neurons. The D(1) dopamine receptor antagonist SCH 23390 blocked the effect of SKF 81297. Membrane-permeant cAMP analogues mimicked the effect of D(1) dopamine receptor stimulation, whereas an inhibitor of protein kinase A (PKA; Rp-8-chloroadenosine 3',5' cyclic monophosphothioate) attenuated the response to D(1) dopamine receptor stimulation or cAMP analogues. Inhibitors of protein phosphatase 1/2A potentiated the modulation by cAMP analogues. Single-cell RT-PCR profiling revealed consistent expression of mRNA for the beta1 subunit of the GABA(A) receptor-a known substrate of PKA-in medium spiny neurons. Immunoprecipitation assays of radiolabeled proteins revealed that D(1) dopamine receptor stimulation increased phosphorylation of GABA(A) receptor beta1/beta3 subunits. The D(1) dopamine receptor-induced phosphorylation of beta1/beta3 subunits was attenuated significantly in neostriata from DARPP-32 mutants. Voltage-clamp recordings corroborated these results, revealing that the efficacy of the D(1) dopamine receptor modulation of GABA(A) currents was reduced in DARPP-32-deficient medium spiny neurons. These results argue that D(1) dopamine receptor stimulation in neostriatal medium spiny neurons reduces postsynaptic GABA(A) receptor currents by activating a PKA/DARPP-32/protein phosphatase 1 signaling cascade targeting GABA(A) receptor beta1 subunits.
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PMID:D(1) dopamine receptor activation reduces GABA(A) receptor currents in neostriatal neurons through a PKA/DARPP-32/PP1 signaling cascade. 1080 95

Using a combination of protein kinase A type II overlay screening, rapid amplification of cDNA ends, and database searches, a contig of 9923 bp was assembled and characterized in which the open reading frame encoded a 1901-amino-acid A-kinase-anchoring protein (AKAP) with an apparent SDS-PAGE mobility of 220 kDa, named human AKAP220 (hAKAP220). The hAKAP220 amino acid sequence revealed high similarity to rat AKAP220 in the 1167 C-terminal residues, but contained 727 residues in the N-terminus not present in the reported rat AKAP220 sequence. The hAKAP220 mRNA was expressed at high levels in human testis and in isolated human pachytene spermatocytes and round spermatids. The hAKAP220 protein was present in human male germ cells and mature sperm. Immunofluorescent labeling with specific antibodies indicated that hAKAP220 was localized in the cytoplasm of premeiotic pachytene spermatocytes and in the centrosome of developing postmeiotic germ cells, while a midpiece/centrosome localization was found in elongating spermatocytes and mature sperm. The hAKAP220 protein together with a fraction of PKA types I and II and protein phosphatase I was resistant to detergent extraction of sperm tails, suggesting an association with cytoskeletal structures. In contrast, S-AKAP84/D-AKAP1, which is also present in the midpiece, was extracted under the same conditions. Anti-hAKAP220 antisera coimmunoprecipitated both type I and type II regulatory subunits of PKA in human testis lysates, indicating that hAKAP220 interacts with both classes of R subunits, either through separate or through a common binding motif(s).
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PMID:Localization of a novel human A-kinase-anchoring protein, hAKAP220, during spermatogenesis. 1086 71

Aurora2 is a cell cycle regulated serine/threonine protein kinase which is overexpressed in many tumor cell lines. We demonstrate that Aurora2 is regulated by phosphorylation in a cell cycle dependent manner. This phosphorylation occurs on a conserved residue, Threonine 288, within the activation loop of the catalytic domain of the kinase and results in a significant increase in the enzymatic activity. Threonine 288 resides within a consensus motif for the cAMP dependent kinase and can be phosphorylated by PKA in vitro. The protein phosphatase 1 is shown to dephosphorylate this site in vitro, and in vivo the phosphorylation of T288 is induced by okadaic acid treatment. Furthermore, we show that the Aurora2 kinase is regulated by proteasome dependent degradation and that Aurora2 phosphorylated on T288 may be targeted for degradation during mitosis. Our experiments suggest that phosphorylation of T288 is important for regulation of the Aurora2 kinase both for its activity and its stability.
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PMID:The mitotic serine/threonine kinase Aurora2/AIK is regulated by phosphorylation and degradation. 1103 8

The role of protein phosphorylation in secretion is not well understood. Here we show that yeast lacking the Snc1,2 v-SNAREs, or bearing a temperature-sensitive mutation in the Sso2 t-SNARE, are rescued at restrictive conditions by the addition of ceramide precursors and analogs to the growth medium. Rescue results from dephosphorylation of the Sso t-SNAREs by a ceramide-activated type 2A protein phosphatase (Sit4) involved in cell cycle control. Sso t-SNARE dephosphorylation correlated with its assembly into complexes with the Sec9 t-SNARE, both in vitro and in vivo, and with an increase in protein trafficking and secretion in cells. SNARE complexes isolated under these conditions contained only Sso and Sec9, suggesting that a t-t-SNARE fusion complex is sufficient to confer exocytosis. Mutation of a single PKA site (Ser79 to Ala79) in Sso1 resulted in a decrease in phosphorylation and was sufficient to confer growth to snc cells at restrictive conditions. Thus, modulation of t-SNARE phosphorylation regulates SNARE complex assembly and membrane fusion in vivo.
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PMID:t-SNARE dephosphorylation promotes SNARE assembly and exocytosis in yeast. 1115 48

Elevation of cAMP promotes the endothelial cell (EC) barrier and protects the lung from edema development. Thus, we tested the hypothesis that both increases and decreases in PKA modulate EC function and coordinate distribution of regulatory, adherence, and cytoskeletal proteins. Inhibition of PKA activity by RpcAMPS and activation by cholera toxin was verified by assay of kemptide phosphorylation in digitonin permeabilized EC. Inhibition of PKA by RpcAMPS or overexpression of the endogenous inhibitor, PKI, decreased monolayer electrical impedance and exacerbated the decreases produced by agonists (thrombin and PMA). RpcAMPS directly increased F-actin content and organization into stress fibers, increased co-staining of actin with both phosphatase 2B and myosin light chain kinase (MLCK), caused reorganization of focal adhesions, and decreased catenin at cell borders. These findings are similar to those evoked by thrombin. In contrast, cholera toxin prevented the agonist-induced resistance decrease and protein redistribution. Although PKA activation attenuated thrombin-induced myosin light chain (MLC) phosphorylation, PKA inhibition per se did not cause MLC phosphorylation or affect [Ca2+]i. These studies indicate that a decrease in PKA activity alone can produce disruption of barrier function via mechanisms not involving MLCK and support a central role for cAMP/PKA in regulation of cytoskeletal and adhesive protein function in EC which correlates with altered barrier function.
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PMID:Regulation of endothelial barrier function by the cAMP-dependent protein kinase. 1120 26

Western blot analyses reveal that calcineurin A (CNA), which is present in the hippocampus, basolateral amygdala, parietal cortex, and MPOA of virgin males and females, is undetectable only in the MPOA of primiparous females regardless of whether they had postpartum pup contact or not. In contrast, CNB was expressed at unchanging levels in the PC and MPOA. Similarly, G(alphao) and PKA(RI) were expressed at high levels in all of the brain regions of virgin males, virgin females, and primiparous females, supporting the concept that this loss of CNA is a specific event. Understanding how and why the expression of CNA, the sole neuronal Ca2+/CaM-dependent protein phosphatase, is down-regulated specifically in the MPOA of primiparous females may yield some insight into the signal transduction events that mediate the onset of mammalian maternal behavior.
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PMID:Loss of calcineurin from the medial preoptic area of primiparous rats. 1123 68

The threshold for hippocampal-dependent synaptic plasticity and memory storage is thought to be determined by the balance between protein phosphorylation and dephosphorylation mediated by the kinase PKA and the phosphatase calcineurin. To establish whether endogenous calcineurin acts as an inhibitory constraint in this balance, we examined the effect of genetically inhibiting calcineurin on plasticity and memory. Using the doxycycline-dependent rtTA system to express a calcineurin inhibitor reversibly in the mouse brain, we find that the transient reduction of calcineurin activity facilitates LTP in vitro and in vivo. This facilitation is PKA dependent and persists over several days in vivo. It is accompanied by enhanced learning and strengthened short- and long-term memory in several hippocampal-dependent spatial and nonspatial tasks. The LTP and memory improvements are reversed fully by suppression of transgene expression. These results demonstrate that endogenous calcineurin constrains LTP and memory.
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PMID:Inducible and reversible enhancement of learning, memory, and long-term potentiation by genetic inhibition of calcineurin. 1125 22


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