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:4.6.1.1 (adenylate cyclase)
19,190 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Until recently, neonatal hyperthyroidism has been considered to be related to the transplacental passage of thyroid-stimulating Ig present in the serum of the mother. We report here the case of a newborn who presented with severe hyperthyroidism, diffuse goiter, and important ocular signs (eyelid retraction and possibly proptosis). However, the absence of thyroid pathology in the parents and the lack of antithyroid antibodies in the mother and in the patient led us to suspect a nonimmune aetiology. Direct genomic sequencing of the last exon of the TSH receptor in the patient revealed a T-->C transversion yielding to a Met453-->Thr heterozygous substitution in the second transmembrane domain of the receptor. The mutation was absent in both parents. Eukaryotic expression analysis in COS-7 cells yielded a mutated receptor that produced constitutive activation of adenylate cyclase without enhancement of phospholipase C activity.
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PMID:A neomutation of the thyroid-stimulating hormone receptor in a severe neonatal hyperthyroidism. 896 21

The specific participation of protein kinases in the expression of the somatic signs of morphine withdrawal has been previously demonstrated, suggesting that changes in intracellular signalling systems are involved in opioid addiction. In the present study, the involvement of protein kinases in the aversive/dysphoric effects of morphine abstinence has been investigated in the nucleus accumbens, because of the critical role played by the mesolimbic system in the rewarding effects of opioids. Rats were chronically treated with morphine, twice a day for 5 days, with doses progressively increased from 5 to 30 mg/kg (i.p.). In addition, microinjections into the nucleus accumbens of the serine-threonine kinase inhibitors H7 or H8 (1 or 10 nmol per side) or saline once daily were also given, both in control and in morphine-treated animals. After these chronic treatments, withdrawal syndrome was induced by naloxone administration (0.1 mg/kg, s.c.), and the motivational component of morphine abstinence was studied using the place aversion paradigm. When administered at the highest dose (10 nmol), H7 and H8 strongly reduced the place aversion induced by naloxone in morphine dependent animals. Protein kinase inhibitors did not induce significant behavioural responses in non-dependent animals. Chronic morphine treatment induced a selective up-regulation of adenylate cyclase activity in the amygdala, without affecting other brain regions. The morphine-increased adenylate cyclase activity in amygdala was reversed by the chronic intra-accumbens microinjections of H7 and H8. These results suggest that serine-threonine kinases in the nucleus accumbens play an important role in the emotional/dysphoric properties which characterize opiate withdrawal.
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PMID:Protein kinases in the rat nucleus accumbens are involved in the aversive component of opiate withdrawal. 899 17

Protein phosphatase 2C (PP2C) is a Mn2+- or Mg2+-dependent protein Ser/Thr phosphatase that is essential for regulating cellular stress responses in eukaryotes. The crystal structure of human PP2C reveals a novel protein fold with a catalytic domain composed of a central beta-sandwich that binds two manganese ions, which is surrounded by alpha-helices. Mn2+-bound water molecules at the binuclear metal centre coordinate the phosphate group of the substrate and provide a nucleophile and general acid in the dephosphorylation reaction. Our model presents a framework for understanding not only the classical Mn2+/Mg2+-dependent protein phosphatases but also the sequence-related domains of mitochondrial pyruvate dehydrogenase phosphatase, the Bacillus subtilus phosphatase SpoIIE and a 300-residue domain within yeast adenyl cyclase. The protein architecture and deduced catalytic mechanism are strikingly similar to the PP1, PP2A, PP2B family of protein Ser/Thr phosphatases, with which PP2C shares no sequence similarity, suggestive of convergent evolution of protein Ser/Thr phosphatases.
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PMID:Crystal structure of the protein serine/threonine phosphatase 2C at 2.0 A resolution. 900 55

Myosin light chain (MLC) phosphorylation catalyzed by the Ca(2+)- calmodulin-dependent MLC kinase (MLCK) is critical to thrombin-mediated endothelial cell gap formation and barrier dysfunction. We have tested the hypothesis that the Ca2+ ionophore ionomycin stimulates MLCK-dependent endothelial cell contraction and permeability. Ionomycin significantly increased albumin clearance and decreased electrical resistance across confluent bovine pulmonary microvascular and macrovascular endothelial cell monolayers in a concentration-dependent manner that was temporally similar to that produced by thrombin. In contrast, however, ionomycin produced a significant Ca(2+)-dependent reduction in the levels of phosphorylated MLC with evidence of serine/threonine phosphatase activation. Potential MLCK-independent mechanisms of endothelial cell permeability were examined with little evidence to support a role for stimulated nitric oxide synthase or phospholipase A2 activities. Importantly, ionomycin produced 1) reductions in the activities of the barrier protective adenylate cyclase and the adenosine 3',5'-cyclic monophosphate-dependent protein kinase A, 2) dramatic dose- and time-dependent inhibition of endothelial cell tyrosine kinase activities, and 3) marked decreases in the phosphotyrosine content of the p125 focal adhesion kinase. These data indicate that ionomycin produces endothelial cell barrier dysfunction by mechanisms that are independent of MLCK activation and may involve reductions in endothelial cell tethering forces via inhibition of protein kinase A and tyrosine kinase activities, especially the p125 focal adhesion kinase.
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PMID:Mechanisms of ionomycin-induced endothelial cell barrier dysfunction. 925 54

Treatment of rat hepatocytes with the phosphatase inhibitors okadaic acid or ortho-vanadate had led to an 80% decrease in the bacterial mutagenicity of several aromatic amines metabolically activated by these hepatocytes. This is the most dramatic change yet demonstrated in mutagenicity by phosphorylation modulation. However, incorporation of phosphate into and catalytic activity of cytochromes P450 (CYP) 1A1 and 1A2, the major catalysts for the first step in the toxication of aromatic amines, were unchanged. We therefore investigated whether changes in the phosphorylation status would influence the activities of the N-acetyltransferases NAT1 and/or NAT2, being responsible for one of the two major pathways leading to the ultimate mutagens, the reactive esters which are derived from the N-hydroxylated metabolites of aromatic amines. Hepatocytes were derived from the livers of rats pretreated with CYP1A1/1A2 inducers and from untreated rats using conditions under which the phosphorylation-dependent drastic decrease of the arylamine mutagenicity was observed. Treatments were exposure to 1 mM dibutyryl-cAMP (protein kinase A stimulator), 100 nM okadaic acid or 20 nM calyculin A (preferential inhibitors of serine/threonine phosphatases PP2A and PP1, respectively), 2 mM ortho-vanadate (inhibitor of tyrosine phosphatases), and 50 mM NaF (stimulator of adenylate cyclase and non-specific inhibitor of protein phosphatases). None of the phosphorylation modulators led to a significant change in NAT1 or NAT2 activities. This was true for hepatocytes from rats which had been pretreated with inducers for CYP1A1 and CYP1A2 as well as from untreated rats. The inducers led to the expected increases in CYP1A1 and CYP1A2 but the NAT1 and NAT2 activities remained unchanged. Our study shows that the N-acetyl transferases NAT1 or NAT2, the catalysts responsible for the formation of the highly reactive N-acetoxy derivatives of N-hydroxylated aromatic amines, are not responsible for the drastic decrease in arylamine genotoxicity after treatment of the metabolizing system with protein phosphatase inhibitors. The data also show that NAT1 and NAT2 are not regulated by the classical xenobiotic metabolizing enzyme inducers nor by any of the phosphorylation modulators used.
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PMID:Control of the mutagenicity of arylamines by protein kinases and phosphatases: II. Lack of response of rat liver N-acetyl transferases to phosphorylation modulators. 933 4

1. The regulation of cardiac Cl- current (ICl) by tyrosine and serine/threonine phosphorylation was examined in guinea-pig and rat ventricular myocytes. The protein tyrosine kinase (PTK) inhibitor genistein (GST) and phosphotyrosine phosphatase (PTP) inhibitor sodium orthovanadate (VO4) were used to modify tyrosine phosphorylation, whereas forskolin (FSK), cAMP, and other agents were used to modify cytoplasmic cAMP concentration and protein kinase A (PKA) phosphorylation. 2. Low concentrations (0.1 microM) of FSK did not activate the PKA-regulated cystic fibrosis transmembrane regulator (CFTR) ICl in guinea-pig ventricular myocytes, but strongly potentiated activation of an ICl by 20-100 microM GST. The potentiation did not occur when GST was replaced by PTK-inactive daidzein, and it was strongly inhibited by 1 mM VO4. 3. Potentiation by 0.1 microM FSK was linked to a small stimulation of the adenylate cyclase-cAMP-PKA pathway. The potentiation was not mimicked by inactive 1,9-dideoxyforskolin, and was inhibited by muscarinic stimulation (ACh) and by a PKA inhibitor. Internal application of a cAMP solution that alone was too weak to activate CFTR ICl strongly potentiated the activation of ICl by 50 microM GST and occluded potentiation by 0.1 microM FSK. 4. The foregoing suggests that potentiated ICl flows through cAMP-dependent CFTR channels. In agreement with this interpretation, GST did not increase ICl when CFTR was maximally activated by a high concentration (5 microM) of FSK and okadaic acid, and neither GST nor GST plus FSK activated an ICl in CFTR-deficient rat myocytes. The lack of effect in rat myocytes was not due to the absence of functional, channel-relevant PKA and PTK-PTP systems, because (as in guinea-pig myocytes) L-type Ca2+ current (ICa,L) was stimulated by FSK and inhibited in a VO4-reversible manner by GST. 5. The synergistic activation of CFTR by low concentrations of FSK and GST cannot be explained by either a GST-induced elevation of cAMP concentration or inhibition of serine/threonine phosphatase. Rather, it appears to be due to tyrosine dephosphorylation that facilitates PKA-mediated phosphorylation of the channels.
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PMID:Synergistic activation of guinea-pig cardiac cystic fibrosis transmembrane conductance regulator by the tyrosine kinase inhibitor genistein and cAMP. 940 69

The mechanisms through which changes in intracellular Ca2+ concentration ([Ca2+]i) might influence desensitization of neuronal nicotinic receptors (nAChRs) of rat chromaffin cells were investigated by simultaneous patch-clamp recording of membrane currents and confocal microscopy imaging of [Ca2+]i induced by nicotine. Increases in [Ca2+]i that were induced by membrane depolarization or occurred spontaneously did not influence inward currents elicited by focally applied test pulses (10 msec) of nicotine, indicating that raised [Ca2+]i per se did not trigger desensitization of nAChRs. Desensitization of nAChRs, evoked by 2 sec focal application of nicotine, which largely raised [Ca2+]i, was not affected by intracellular application of agents that activate or depress protein kinase C (PKC) or A (PKA) or inhibit phosphatase 1, 2 A and B. Conversely, recovery from desensitization was facilitated by the phorbol ester phorbol 12-myristate 13-acetate (PMA) or the phosphatase 2 B inhibiting complex of cyclosporin A-cyclophilin A, whereas it was impaired by the broad spectrum kinase inhibitor staurosporine. The effects of PMA or staurosporine were prevented by the intracellularly applied Ca2+ chelator BAPTA. The adenylate cyclase activator forskolin accelerated recovery, whereas the selective PKA antagonist Rp-cAMPS had an opposite effect. The action of staurosporine and Rp-cAMPS on recovery from desensitization was additive. It is proposed that when nAChRs are desensitized, they become susceptible to modulation by [Ca2+]i via intracellular second messengers such as serine/threonine kinases and calcineurin. Thus, the phosphorylation state of neuronal nAChRs appears to regulate their rate of recovery from desensitization.
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PMID:Recovery from desensitization of neuronal nicotinic acetylcholine receptors of rat chromaffin cells is modulated by intracellular calcium through distinct second messengers. 950 6

A sequence motif of 20 amino acid residues within the C-terminal portion of the rat somatostatin receptor subtype 4 (SSTR4) has been shown to prevent rapid agonist-dependent receptor internalization in transfected human embryonic kidney (HEK) cells. Molecular dissection of this motif by biochemical ligand-binding assays revealed that the block was released by mutating a single residue (threonine 331) to an alanine. These data are in line with confocal microscopic analysis of cultured primary neurons microinjected with cDNA constructs encoding either SSTR4 or the mutant T331A. Immunocytochemical analysis showed that the mutant receptor, but not SSTR4, was internalized. However, internalized T331A was not recycled to the cell surface, suggesting that it lacks sequence elements that determine intracellular sorting after endocytosis. Neither wildtype SSTR nor the mutant T331A exhibited functional desensitization when assayed for their ability to inhibit adenylate cyclase. In agreement with this, the wt receptor and its mutant were not phosphorylated in response to agonist treatment. Lack of desensitization of SSTR4 has been electrophysiologically verified by coexpressing the receptor with a G-protein-gated, inwardly rectifying potassium channel in Xenopus oocytes. A strong somatostatin 14 (SST14)-activated inward potassium current was observed that was long-lasting and which decayed only slowly after washout of the agonist. This is in contrast to another somatostatin receptor subtype, SSTR3, which mediates rapidly desensitizing currents. Binding experiments on HEK cells transfected with either SSTR3 or 4 indicated that this difference is not attributable to slow dissociation of the agonist from the receptor, suggesting that SSTR4 mediates long-lasting signalling, a property which may be relevant for clinical therapy.
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PMID:Rat somatostatin receptor subtype 4 can be made sensitive to agonist-induced internalization by mutation of a single threonine (residue 331). 980 48

The human beta-adrenoceptor is a member of the seven-transmembrane family of receptors, encoded by a gene on chromosome 5. beta-Adrenoceptors have been classified into beta1, beta2, and beta3 subgroups, with beta2-receptors being widely distributed in the respiratory tract, particularly in airway smooth muscle. Intracellular signaling following beta2-adrenoceptor activation is largely affected through a trimeric Gs protein coupled to adenylate cyclase. Cyclic AMP (cAMP) induces airway relaxation through phosphorylation of muscle regulatory proteins and attenuation of cellular Ca2+ concentrations. Alternative cAMP-independent pathways involving activation of membrane maxi-K+ channels and coupling through Gi to the MAP kinase system have also been described. Site-directed mutagenesis has identified Asp 113 and Ser 204/207 within the third and fourth membrane domains as the active site of the beta2-receptor, critical for beta2-agonist binding and activity. beta2-Agonists have been characterized as those that directly activate the receptor (albuterol), those that are taken up into a membrane depot (formoterol), and those that interact with a receptor-specific auxiliary binding site (salmeterol). These differences in mechanism of action are reflected in the kinetics of airway smooth muscle relaxation and bronchodilation in patients with asthma. beta-Adrenoceptor desensitization associated with beta2-agonist activation is a consequence of phosphorylation by beta-ARK and uncoupling of the receptor from Gs following beta-arrestin binding, of internalization and recycling of the receptor through processes of sequestration and resensitization and downregulation, modulated by an effect on receptor gene expression. The degree of receptor desensitization appears to differ, depending on the cell or tissue type, and is reflected in the different profiles of clinical tolerance to chronic beta2-agonist therapy. A number of polymorphisms of the beta2-receptor have been described that appear to alter the behavior of the receptor following agonist exposure. These include Arg-Gly 16, Glu-Gln 27, and Thr-lle 164. The Gly 16 receptor downregulates to a greater extent and is associated with increased airway hyperreactivity, nocturnal symptoms, and more severe asthma. The Glu 27 form appears to protect against downregulation and is associated with less reactive airways. An individual can be homozygous or heterozygous for given polymorphisms, and large populations will have to be studied to determine their importance to the asthma phenotype.
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PMID:The beta-adrenoceptor. 981 38

Chronic exposure of sheep adipose tissue to growth hormone (GH) in vitro decreases the ability of the adenosine analogue, N6-phenylisopropyladenosine (PIA), to inhibit isoprenaline-stimulated lipolysis by a mechanism which is dependent on both gene transcription and protein serine/threonine phosphorylation. The inhibition is not due to a change in ligand binding to the adenosine receptor, the amounts of the three isoforms of the inhibitory GTP-binding protein, Gi, or the maximum (forskolin-stimulated) adenylate cyclase activity. The ability of GH to modulate the PIA-activated adenosine receptor to stimulate dissociation of heterotrimeric Gi was assessed by measurement of pertussis toxin-catalysed ADP-ribosylation of Gi; GH does not appear to alter the interaction between the activated receptor and Gi. The ability of GH to alter the ability of activated Gi to inhibit adenylate cyclase activity was assessed by measuring the ability of a GTP analogue, guanosine 5'-[beta gamma-imido]triphosphate (p[NH]ppG), to inhibit forskolin-stimulated adenylate cyclase activity; chronic exposure to GH prevented this effect of p[NH]ppG. Thus the attenuation of the inhibition of lipolysis by PIA by chronic exposure of adipocytes to GH appears to be due to an impairment in the interaction between adenylate cyclase and the alpha subunit of one or more isoforms of Gi.
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PMID:Regulation of the GTP-binding protein-based antilipolytic system of sheep adipocytes by growth hormone. 984 58


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