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)

Many hormones act on neuroendocrine cells by activating second messenger pathways. Two of these, the phosphoinositol and cAMP-dependent pathways, cause changes in cellular activity through specific protein kinases. By phosphorylating cytoplasmic and nuclear proteins, these kinases apparently coordinate cellular processes, including the biosynthesis and release of neuropeptides. Somatostatin biosynthesis and release, for example, are both positively regulated by the second messenger cAMP in hypothalamic cells, and cAMP also induces somatostatin gene transcription 8-10-fold in transfected PC12 pheochromocytoma cells. Transcriptional induction requires a 30-nucleotide cAMP response element (CRE) which is conserved in other cAMP-responsive genes. This element also confers cAMP responsiveness when placed upstream of the heterologous simian virus 40 (SV40) promoter. The somatostatin gene does not, however, respond to cAMP in mutant PC12 cells which lack cAMP-dependent protein kinase type II activity. Activation of somatostatin gene transcription may consequently require the phosphorylation of a nuclear protein which binds to the CRE. Using a DNase I protection assay, we have characterized a nuclear protein in PC12 cells which binds selectively to the CRE in the somatostatin gene. We have purified this protein which is of relative molecular mass 43,000 (Mr 43K) by sequence-specific DNA affinity chromatography. This 43K CRE binding protein (CREB) is phosphorylated in vitro when it is incubated with the catalytic subunit of cAMP-dependent protein kinase. Stimulating PC12 cells with forskolin, an activator of adenyl cyclase, causes a 3-4-fold increase in the phosphorylation of this protein. We conclude that the cAMP-dependent pathway may regulate gene transcription in response to hormonal stimulation by phosphorylating this CREB protein.
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PMID:Binding of a nuclear protein to the cyclic-AMP response element of the somatostatin gene. 288 56

Interleukin 2 (IL 2) stimulated DNA synthesis of murine T lymphocytes (CT6) in a concentration-dependent manner, over a range of 1-1000 units/ml. This proliferative effect of IL 2 was attenuated by simultaneous exposure to prostaglandin E2 (PGE)2. In intact cells, IL 2 inhibited both basal and PGE2-stimulated cAMP production; the amount of cAMP generated was dependent upon the relative concentrations of IL 2 and PGE2. The effect of IL 2 on CT6 cell proliferation and cAMP production was mimicked by the phorbol ester 12-O-tetradecanoylphorbol-13-acetate (TPA), which, like IL 2, causes a translocation and activation of protein kinase C. While PGE2 stimulated adenylate cyclase activity in membrane preparations, neither IL 2 nor TPA inhibited either basal or stimulated membrane adenylate cyclase activity. However, when CT6 cells were pretreated with IL 2 or TPA and membranes incubated with calcium and ATP, both basal and PGE2-and NaF-stimulated membrane adenylate cyclase activity was inhibited. This inhibition of adenylate cyclase activity was also observed if membranes from untreated cells were incubated with protein kinase C purified from CT6 lymphocytes in the presence of calcium and ATP. The data suggest that the decreased cAMP production which accompanies CT6 cell proliferation results from an inhibition of adenylate cyclase activity mediated by protein kinase C and that these two distinct protein phosphorylating systems interact to modulate the physiological response to IL 2.
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PMID:Interleukin 2 modulation of adenylate cyclase. Potential role of protein kinase C. 300 78

The structural components involved in transduction of extracellular signals as diverse as a photon of light impinging on the retina or a hormone molecule impinging on a cell have been highly conserved. These components include a recognition unit or receptor (for example, the beta-adrenergic receptor (beta AR) for catecholamines or the 'light receptor' rhodopsin), a guanine nucleotide regulatory or transducing protein, and an effector enzyme (for example, adenylate cyclase or cyclic GMP phosphodiesterase). Molecular cloning has revealed that the beta AR shares significant sequence and three-dimensional homology with rhodopsin. The function of the beta AR is diminished by exposure to stimulatory agonists, leading to desensitization. Similarly, 'light adaptation' involves decreased coupling of photoactivated rhodopsin to cGMP phosphodiesterase activation. Both forms of desensitization involve receptor phosphorylation. The latter is mediated by a unique protein kinase, rhodopsin kinase, which phosphorylates only the light-bleached form of rhodopsin. An analogous enzyme (termed beta AR kinase or beta ARK) phosphorylates only the agonist-occupied beta AR. We report here that beta ARK is also capable of phosphorylating rhodopsin in a totally light-dependent fashion. Moreover, rhodopsin kinase can phosphorylate the agonist-occupied beta AR. Thus the mechanisms which regulate the function of these disparate signalling systems also appear to be similar.
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PMID:Light-dependent phosphorylation of rhodopsin by beta-adrenergic receptor kinase. 301 40

The cyclic AMP-activated protein kinase I, a serine- and threonine-phosphorylating enzyme, regulates cell-to-cell communication. Its deficiency in mutant cells is associated with deficiency of communication. The communication defect is corrected by introduction of the catalytic subunit of the enzyme into the mutant cells. Activation of the enzyme by cyclic AMP in normal cells causes an increase of communication, namely an increase of junctional permeability associated with an increase in the number of membrane particles of gap junction. This upregulation of cell-to-cell membrane channels constitutes a basic mechanism whereby cell communities set their degree of communication. The mechanism is normally put into motion by adenylate cyclase-activating hormones. The mechanism is counteracted by tyrosine-phosphorylating protein kinase (src protein), which downregulates junctional permeability, a fast and reversible effect on the channels, independent of the action of the kinase on the cytoskeleton. The two T proteins coded by the SV-40 genome cause a similar channel downregulation.
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PMID:Regulation of cell-to-cell communication by phosphorylation. 301 52

Mounting evidence suggests that the physiological function of the various subtypes of adrenergic receptors is controlled by phosphorylation/dephosphorylation reactions. It seems intuitively unlikely that this phenomenon will be limited simply to the adrenergic receptors, since these receptors share transmembrane signaling pathways with a host of other plasma membrane receptors. Different types of kinases appear to be involved. On the one hand, phosphorylation reactions may operate in a classical feedback regulatory sense. Thus, the cAMP-dependent protein kinase, once activated by a beta-agonist, can feedback-regulate the function of the receptors by phosphorylating and desensitizing them. Similarly, protein kinase C appears to be able to feedback-regulate the function of alpha 1-adrenergic receptors by phosphorylation. There may also be "cross talk" between the systems. Thus, protein kinase C, when stimulated by phorbols, is able to phosphorylate and desensitize the beta-adrenergic receptors. Moreover, very recently we have found that the cAMP-dependent protein kinase can phosphorylate the alpha 1-adrenergic receptors in vitro. These are examples of one transmembrane signaling system regulating the function of another. Perhaps most interestingly, it appears that there may be a previously unappreciated class of receptor kinases in the cytosol of cells. The first of these, which we have recently found and named beta-ARK, serves to phosphorylate only the agonist-occupied form of the beta-adrenergic receptor. As noted, it is somewhat analogous to the rhodopsin kinase. Such highly specific receptor kinases, which can phosphorylate only the agonist-occupied form of a receptor, represent a potentially elegant mechanism for controlling the function of receptors in a fashion which is linked to their physiological stimulation. How widespread such kinases are, and the actual roles which they play in regulating receptor function, remain to be determined. Finally, it should be stressed that although this review has focused on the regulatory role of receptor phosphorylation, it is by no means our intent to suggest that receptors are the only locus for physiological control of sensitivity to hormone and drug reaction. There is already evidence that guanine nucleotide regulatory proteins can be regulated, and it seems likely that each of the components of the system, including the adenylate cyclase, are likely to be involved in various forms of complex regulation. To date, however, the receptors represent that component of the system whose regulation we understand in the greatest detail.
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PMID:Regulation of adrenergic receptor function by phosphorylation. 302 10

Second-messenger systems play a major role in mediating neurotransmitter actions. In recent years our understanding of the organization and function of two prominent second-messenger systems has progressed rapidly--the adenylate cyclase and phosphoinositide systems. Guanosine triphosphate-binding proteins, which are especially abundant in brain, couple transmitter receptors to the key second-messenger generating enzymes in both of these systems. Whereas activation of adenylate cyclase produces a single intracellular messenger, cyclic AMP, stimulation of the phosphoinositide system generates at least two, inositol trisphosphate and diacylglycerol. Inositol trisphosphate mobilizes calcium from intracellular stores, and diacylglycerol, like cyclic adenosine monophosphate, activates a phosphorylating enzyme, protein kinase C. These second-messenger systems are particularly enriched in the brain where they modulate many aspects of synaptic transmission.
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PMID:Beyond receptors: multiple second-messenger systems in brain. 303 86

The effects of 3 phosphodiesterase inhibitors, aminophylline, isobutylmethylxanthine (IBMX), and RO 20-1724, were tested on descending intraspinal and spinal reflex transmission to sympathetic preganglionic neurons in unanesthetized spinal cats. Sympathetic discharges, recorded from upper thoracic preganglionic white rami, were evoked by stimulation (0.1 Hz) of descending excitatory pathways in the cervical dorsolateral funiculus (intraspinal) or of adjacent intercostal nerves (spinal reflex). Each phosphodiesterase rapidly and markedly enhanced transmission through intraspinal pathways but only slowly and modestly enhanced transmission through spinal reflex pathways. Pretreatment with a methyltyrosine-reserpine combination, chlorpromazine, or prazosin markedly restricted the enhancement of intraspinal transmission by IBMX to levels typically produced on spinal reflex pathways. Clonidine markedly depressed transmission through both pathways and prevented enhancement by the phosphodiesterase inhibitors. Yohimbine or tolazoline antagonized the depressant effects of clonidine and restored the ability of the phosphodiesterase inhibitors to enhance transmission. Somatic spinal reflexes were not affected by the phosphodiesterase inhibitors. The results suggest that descending norepinephrine pathways to sympathetic preganglionic neurons activate adenylate cyclase to generate cyclic AMP which increases neuronal excitability, possibly by phosphorylating membrane proteins. Clonidine appears to depress neuronal excitability by inhibiting adenylate cyclase through activation of alpha 2-adrenergic receptors.
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PMID:Enhancement of central transmission to sympathetic preganglionic neurons by phosphodiesterase inhibitors and its prevention by clonidine. 304 Aug 47

Addition of phorbol ester-activated, partially purified protein kinase C to membranes of human platelets had no effect on forskolin stimulation of the adenylate cyclase and increased stimulation by prostaglandin E1 only at high GTP concentrations by preventing inhibition by GTP. Hormonal inhibition of the platelet adenylate cyclase by epinephrine was eliminated or largely impaired. At low GTP concentrations, epinephrine even caused a small increase in cyclase activity. The data suggest that activated protein kinase C interferes with GTP- and hormone-induced adenylate cyclase inhibition probably by phosphorylating the inhibitory guanine nucleotide-binding regulatory component Ni.
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PMID:Protein kinase C interferes with Ni-mediated inhibition of human platelet adenylate cyclase. 405 15

The plasma membrane of the bovine renal collecting duct epithelial cell has been resolved into its apical (luminal) and basal-lateral (contraluminal) components by free flow electrophoresis. The contraluminal, but not the luminal, membrane was found to contain antidiuretic hormone-sensitive adenylate cyclase. The luminal membrane was found to contain a cyclic 3':5'-adenosine monophosphate-sensitive self-phosphorylating system consisting of a membrane-bound protein kinase and its membrane-bound substrate(s); this intrinsic protein kinase was not present in the contraluminal membrane. These findings provide direct evidence that the initiating steps in the action of antidiuretic hormone on the kidney take place at the contraluminal pole of the hormonesensitive target cell and that the late or terminal steps occur at the luminal pole, where they involve an alteration in the level of membrane phosphorylation.
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PMID:Target cell polarity and membrane phosphorylation in relation to the mechanism of action of antidiuretic hormone. 436 61

A conformational change of the antigen receptors takes place with the help of macrophages, T helper cells and soluble factors after antigen binding. This conformational change may result in the following reactions: a) activation of a receptor-associated enzyme system b) influence on the lipid matrix and indirect activation of membrane-associated enzyme systems or influence on the cell metabolism by changing the ion flux c) activation of the cytoskeleton with following movements of the ligand-receptor-complexes and indirect activation of cytoskeleton-associated enzyme systems or influence on the metabolism by changing the ion flux. The adenylate cyclase (phosphorylating cascade) or the proteases (limited proteolysis of inactive proenzymes) may be the enzyme systems with regulatory effect which can be activated.
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PMID:[Biochemical processes on membranes during lymphocyte stimulation]. 622 11


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