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)

Myosin light chain kinase which phosphorylates g2 light chain of skeletal muscle myosin requires an activator for the activity (Yazawa, M., and Yagi, K (1977) J. Biochem. (Tokyo) 82, 287-289). This activator has now been identified as the modulator protein known to be a Ca2+-dependent regulator for phosphodiesterase, adenylate cyclase, and ATPases. The identification is based on the quantitative cross-reactivity of muscle activator protein and brain modulator protein in activating myosin light chain kinase and brain phosphodiesterase and identical properties of both proteins in regard to sensitivities to Ca2+, UV absorption spectra, UV absorption difference spectra with or without Ca2+, and mobilities upon sodium dodecyl sulfate-polyacrylamide gel electrophoresis. In the presence of modulator protein, the activity of myosin light chain kinase was reversibly controlled by the physiological concentration of Ca2+. We suggest that two Ca2+-receptive proteins, i.e. modulator protein and troponin-C, may play roles in the contraction-relaxation cycle of skeletal muscle.
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PMID:Identification of an activator protein for myosin light chain kinase as the Ca2+-dependent modulator protein. 62 40

We propose a mechanism for the cytoplasmic Ca++ oscillator which is thought to power shuttle streaming in strands of the slime-mold Physarum polycephalum. The mechanism uses a phosphorylation-dephosphorylation cycle of myosin light chain kinase. This kinase is bistable if the kinase phosphorylation chain, through adenylate cyclase and cAMP, is activated by calcium. Relaxation oscillations can then occur if calcium is exchanged between the cytoplasm and internal vacuoles known to exist in physarum. As contractile activity in physarum myosin is inhibited by calcium, this model can give calcium oscillations 180 degrees out of phase with actin filament tension as observed. Oscillations of ATP concentration are correctly predicted to be in phase with the tension, provided the actomyosin cycling rate is comparable with ATPase rates for phosphorylation of the myosin light chain and its kinase.
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PMID:Model of the Ca2+ oscillator for shuttle streaming in Physarum polycephalum. 153 35

We have demonstrated that ISO produces part of its negative inotropic action through activation of the plasmalemmal Na+/K+ pump, and reduction of [Na+]i. This action is mediated by the beta-adrenergic receptor through activation of adenylate cyclase. The reduction of [Na+]i is most probably translated to a change in the contractile state of the cell through activation of the Na+/Ca2+ exchanger. While the exchanger is at equilibrium when the cell is at rest, after ISO it would extrude Ca2+ at the expense of the increased Na+ gradient, resulting in a decrease Ca2+ availability and a reduction in the magnitude of subsequent contractions. We have also seen that the previous calcium history of the myoplasm can influence the time course of future calcium transients. Prolonged large increases in [Ca2+]i can accelerate the rate of its removal and depress basal [Ca2+]i levels. This action is most probably mediated through a Ca2+/calmodulin dependent protein kinase. We have observed that MLCK is both necessary and sufficient to produce contraction of Bufo marinus stomach smooth muscle. There is also evidence that an as yet unidentified Ca(2+)-calmodulin dependent protein kinase is acting to limit the magnitude and the duration of the Ca2+ transient by feeding back on processes involved in Ca2+ signal generation.
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PMID:Calcium homeostasis in single intact smooth muscle cells. 180 98

The role of platelets in hemostasis and thrombosis has been well established since Eberth's and Schimmelbusch's pioneering intravital microscopic experiments. A century ago the distinct features of the circulating "smooth disc" and the activated "spiny sphere" were described. Since then the underlying cell-biological processes transforming a harmless floating platelet into a sticky corpuscle, ready to release its stores of thrombogenic and atherogenic substances have been unveiled. However, its life-threatening capabilities have evolved from the necessity of preventing equally dangerous blood losses from a pressurized circulation system. As circulation depends on the liquid state of blood, the platelets and the molecules of the plasmatic coagulation system must circulate in an inactive state, to become activated at the site of "demand" to transform the liquid into a solid hemostatic plug. As in nucleated cells the plasma membrane, made up of a phospholipid bilayer with integrated glycoproteins, is the structure signalling environmental information to the platelet interior. Many of the receptors for stimulatory or inhibitory mediators elicit a cell-biological response via G-proteins and subsequent Ca2+ mobilization by IP3, or stimulation/inhibition of adenylate cyclase followed by changes in cytoplasmic levels of cyclic AMP. The supposed intracellular Ca2+ store of the platelets, the dense tubular system, also appears as the site of Ca2(+)-activated prostaglandin synthesis. Raised cytoplasmic Ca2+ levels promote the polymerization of G-actin to F-actin involved in the extension of pseudopodia in the course of "external shape change." Ca2(+)-activated myosin light-chain kinase phosphorylates myosin which becomes associated with F-actin, with the resulting acto-myosin complex providing the contractile force for "internal shape change," i.e., the centralization of organelles and for clot retraction later in hemostasis. More than by the three-dimensional actin cytoskeleton proper, the discoid shape typical of the nonstimulated platelet appears to be secured by a two-dimensional membrane skeleton of actin filaments anchored to membrane glycoproteins via actin-binding protein or spectrin and ankyrin. Although the microtubule coil has been confirmed as the main determinant of the mechanical stiffness of the platelet with biophysical techniques, its hitherto assumed role for the maintenance of the disc shape no longer appears tenable. The morphological phenomenon of the shape change comprises an alteration of membrane glycoproteins resulting in binding of "adhesive" molecules like fibrinogen.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Histophysiology of the circulating platelet. 226

Nanomolar concentrations of synthetic peptides corresponding to the calmodulin-binding domain of skeletal muscle myosin light chain kinase were found to inhibit calmodulin activation of seven well-characterized calmodulin-dependent enzymes: brain 61 kDa cyclic nucleotide phosphodiesterase, brain adenylate cyclase, Bordetella pertussis adenylate cyclase, red blood cell membrane Ca++-pump ATPase, brain calmodulin-dependent protein phosphatase (calcineurin), skeletal muscle phosphorylase b kinase, and brain multifunctional Ca++ (calmodulin)-dependent protein kinase. Inhibition could be entirely overcome by the addition of excess calmodulin. Thus, the myosin light chain kinase peptides used in this study may be useful antagonists for studying calmodulin-dependent enzymes and processes.
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PMID:Synthetic peptides based on the calmodulin-binding domain of myosin light chain kinase inhibit activation of other calmodulin-dependent enzymes. 290 35

Many hormones and neurotransmitters exert their biological effects by increasing the levels of Ca2+ and 1,2-diacylglycerol in their target cells. Major agonists that act in this way are epinephrine and norepinephrine, acetylcholine, vasopressin, cholecystokinin, and angiotensin II. These and other Ca2+-mobilizing agonists may also produce effects that are not mediated by Ca2+ or diacylglycerol, but involve separate receptors and an increase or decrease in cyclic AMP. The general mechanisms by which Ca2+-mobilizing agonists induce their physiological responses are depicted in Fig. 12. These responses appear to involve an initial mobilization of Ca2+ from endoplasmic reticulum and perhaps other intracellular Ca2+ stores, followed by alterations in the flux of Ca2+ across the plasma membrane. The Ca2+ changes are consistently associated with increased turnover of cellular phosphoinositides. The most rapid response is breakdown of phosphatidylinositol 4,5-P2 in the plasma membrane, and there is much evidence that this involves a guanine-nucleotide-binding regulatory protein similar to those involved in the regulation of adenylate cyclase. Myo-inositol 1,4,5-P3 produced by phosphatidylinositol 4,5-P2 breakdown rapidly releases Ca2+ from endoplasmic reticulum, and it is likely that it is the long-sought second message for the Ca2+-dependent hormones. 1,2-Diacylglycerol, the other product of phosphatidylinositol 4,5-P2 breakdown, also acts as a second message in that it activates protein kinase C, a Ca2+-phospholipid-dependent protein kinase, by lowering its requirement for Ca2+. The cellular substrates for protein kinase C and its role in the different physiological responses to the Ca2+-mediated agonists are currently being defined. The major intracellular target for Ca2+ is the Ca2+-dependent regulatory protein calmodulin. This binds Ca2+ with high affinity, and the resulting complex interacts with a variety of enzymes and other cellular proteins, modifying their activities. A major target is the multifunctional calmodulin-dependent protein kinase that phosphorylates and alters the activities of many proteins, for example, glycogen synthase and tyrosine hydroxylase. Calcium ions may also stimulate calmodulin-dependent protein kinases that are more specific, such as phosphorylase kinase and myosin light-chain kinase. Other important Ca2+-calmodulin targets are the microtubule-associated proteins, but it is likely that many more will be found.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Mechanisms involved in calcium-mobilizing agonist responses. 302 85

Ro 22-4839, a new cerebral circulation improver, has shown to be a potent calmodulin antagonist toward myosin light chain kinase (MLCK). It inhibited in vitro activity of calmodulin-activated cyclic AMP phosphodiesterase isolated from either bovine heart or brain and ATP-induced superprecipitation of chicken gizzard actomyosin with respective IC50 values of 20 microM, 17 microM, and 2.0 microM. The inhibitory action of Ro 22-4839 on the contractile system of the smooth muscle was demonstrated directly by its inhibition of chicken gizzard MLCK. Ro 22-4839 was found to potently inhibit MLCK with an IC50 value of 3.1 microM but was unable to inhibit the activity of MLCK rendered Ca2+/calmodulin independent by limited tryptic digestion. The inhibition of MLCK induced by Ro 22-4839 was completely overcome by addition of excess calmodulin. In contrast, Ro 22-4839 hardly inhibited calmodulin-activated Ca2+, Mg2+-ATPase from rat erythrocyte membrane or adenylate cyclase from rat brain. Use of hydrophobic fluorescence probes showed that Ro 22-4839 binds to the hydrophobic region of calmodulin like other calmodulin antagonists, trifluoperazine and W-7. However, the precise binding site of Ro 22-4839 to calmodulin is different from those of trifluoperazine and W-7, as suggested from differing IC50 values of these compounds against the probes. We conclude that Ro 22-4839 inhibits calmodulin-activated enzymes, most significantly of MLCK, highly specific to smooth muscle contractile systems by binding to the hydrophobic domain of the calmodulin and inducing its conformational change in the presence of calcium.
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PMID:Selective calmodulin inhibition toward myosin light chain kinase by a new cerebral circulation improver, Ro 22-4839. 303 98

In this study a synthetic analog of the calmodulin-binding domain of myosin light chain kinase, a 17-amino-acid peptide (M5) was used to examine the possible role of calmodulin in melanotropin receptor function. Binding of beta-melanocyte-stimulating hormone to its membrane receptor and subsequent stimulation of adenylate cyclase (AC) were found to be specifically inhibited by M5 in a dose-dependent and noncompetitive manner, both in intact M2R melanoma cells and in a plasma membrane preparation derived thereof. Half-maximal inhibition of both hormone binding and melanotropin-sensitive AC activity was shown to occur at approximately 1 microM M5. In contrast, stimulation of AC by prostaglandin E1, guanosine 5'-O-(3-thio)triphosphate, forskolin, and unstimulated enzyme activity were unaffected by the presence of M5, under the same assay conditions. Furthermore, addition of a molar excess of calmodulin to the AC assay completely abolished the inhibitory effects of the peptide on melanotropin-stimulated AC activity. Other peptides of similar size, which bind to calmodulin with low affinity (e.g. glucagon, somatostatin, and vasoactive intestinal peptide), were shown to be totally ineffective in inhibiting melanotropin-sensitive AC. These findings, along with those shown previously for other antagonists of calmodulin, suggest a role for an M5-binding protein, as of yet unidentified, involved in the regulation of the melanotropin receptor function.
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PMID:A synthetic analog of the calmodulin-binding domain of myosin light chain kinase inhibits melanotropin receptor function and activation of adenylate cyclase. 336 68

The cyclic interactions between myosin cross bridges and the actin filament in the presence of Ca++ with a sliding of both filaments passed each other, is considered also in vascular smooth muscle as the basic contractile mechanism. While in the striated muscle the regulation of the actin-myosin interaction occurs at the level of the actin filaments, there is a growing body of evidence that the contractile activation of the vascular smooth muscle is primarily regulated by phosphorylation of the 20,000-Dalton myosin light chain. This reaction is catalyzed by a calcium-calmodulin-dependent myosin light chain kinase. Additionally, dephosphorylated myosin cross bridges which remain attached to actin filaments over prolonged periods of time ("latch bridges") at low myoplasmic Ca2+-concentrations seem to be involved in the vascular smooth muscle in maintaining tonic active stress at a very low energy expenditure. In most arterial smooth muscle cells, the initiation of contraction (electromechanical coupling) is not associated with action potentials, but is coupled with graded membrane depolarization. During the process of excitation-contraction coupling, two mechanisms lead to increased myoplasmic calcium: a) Calcium influx through voltage-dependent channels along an electro-chemical gradient. b) Release of calcium from the sarcoplasmic reticulum or from the inside of the cell membrane, triggered either by calcium influx or directly by membrane depolarization. The pharmaco-mechanical coupling, i.e., the contractile activation by drugs without depolarization as initiating step, seems to be realized only in a few specific vessels. The stimulation of the phosphatidyl-inositol turnover (PI-cycle) in the plasma membrane by activation of alpha 1-adrenergic receptors can also be demonstrated in vascular smooth muscle cells. However, whether or not this PI-response plays a primary role in the increase of myoplasmic Ca2+ remains to be settled. The activation of alpha 2-adrenergic receptors seems to involve the action of an inhibitory guanine nucleotide-binding protein on the catalytic moiety of the adenylate cyclase. Thus, the contractile response observed may be attributed to the decrease of cyclic AMP (which is responsible for dilating effects via phosphorylation of various regulatory proteins). The decrease in the myoplasmic concentration of free-ionized calcium as a basic principle of relaxation comes about by different mechanisms, which can be classified as follows: a) Inhibition of transmembrane calcium influx into vascular smooth muscle cells by Ca-antagonists, which specifically interfere with plasmalemmal Ca2+-channels.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:[Modulation of coronary vessel tonus: molecular and cellular mechanisms]. 609 97

Forskolin, an activator of adenylate cyclase, inhibited contractures induced in rat aorta by norepinephrine (NE) and angiotensin II and by KCl depolarization. The concentration of forskolin required to inhibit NE-induced contractures was significantly lower than required to inhibit KCl-induced contractures (IC50 0.18 +/- 0.01 vs. 2.2 +/- 0.2 microM). Forskolin effectively relaxed NE-induced contractures when active Na+-K+ transport was inhibited. Stimulation of 42K and 36Cl effluxes by NE was inhibited by low concentrations of forskolin. The IC50 for forskolin inhibition of 42K efflux, 0.17 +/- 0.02 M, was similar to that for relaxation of NE contraction. The time course for forskolin-induced increases in adenosine 3',5'-cyclic monophosphate (cAMP) was consistent with that for forskolin-mediated relaxation and its maintenance. Fifty percent inhibition of both NE-induced contractures and NE-stimulated 42K effluxes occurred at levels of cAMP that were 1.4 times basal, and 90% inhibition of both processes was associated with a two to threefold increase in cAMP content. In sharp contrast, the level of tissue cAMP associated with inhibition of KCl contractures was 6-10 times higher than that associated with inhibition of NE-induced contractures. We postulate that cAMP-dependent regulation of membrane fluxes stimulated by receptor occupancy represents a primary mechanism for relaxation of a NE contracture, whereas the processes that regulate depolarization-dependent channels and the phosphorylation of myosin light chain kinase occur at much higher cAMP content and apparently function in a secondary capacity.
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PMID:cAMP-dependent reduction in membrane fluxes during relaxation of arterial smooth muscle. 632 Jun 82


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