Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:2.7.11.1 (protein kinase)
 81,284 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Effects of a series of novel inhibitors of calmodulin or protein kinases on amylase release were studied in rat parotid slices. Amylase release induced by a cholinergic agonist, carbamylcholine, was inhibited by N-(6-aminohexyl)-5-chloro-1-naphthalenesulfonamide (W-7), a calmodulin inhibitor, 1-(5-chloronaphthalen-1-sulfonyl)-1H-hexahydro-1, 4-diazepine (ML-9), a myosin light chain kinase (MLCK) inhibitor, and 1-(5-isoquinolinylsulfonyl)-2-methylpiperazine (H-7), an inhibitor of Ca(2+)-activated, phospholipid-dependent protein kinase (protein kinase C), while N-[2-(methylamino)ethyl]-5-isoquinolinesulfonamide (H-8), an inhibitor of cyclic AMP-dependent protein kinase (protein kinase A), did not inhibit the release. On the other hand, amylase release induced by a beta-adrenergic agonist, isoproterenol, was inhibited only by H-8, but not by W-7, ML-9 or H-7. These results suggest that cholinergic stimulation evokes amylase release via the Ca(2+)-dependent system which involves calmodulin, MLCK and protein kinase C, while beta-adrenergic stimulation via the cyclic AMP-dependent system involves protein kinase A.
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PMID:Effects of inhibitors of intracellular messenger systems on amylase release from rat parotid gland. 171 7

W-66 (N-(2-aminoethyl)-N-[2-(4-chlorocinnamylamino) ethyl]-5-isoquinolinesulfonamide), a newly synthesized isoquinolinesulfonamide, was shown to have a potent vasodilatory action and calmodulin (CaM)-antagonizing action. Using the W-66 affinity chromatographic technique, we purified two Ca(2+)-binding proteins from the EGTA-soluble fraction of bovine aorta. One was CaM and the other was an acidic protein with a molecular mass of 11 kDa. It was tentatively named "calvasculin." Calvasculin was a dimeric protein. Equilibrium dialysis showed that 1 mol of calvasculin (dimer) bound to 1.98 +/- 0.30 mol of Ca2+ in the presence of 10(-3) M Ca2+. Calvasculin failed to activate Ca2+/CaM-dependent enzymes such as myosin light chain kinase, Ca2+/CaM-dependent phosphodiesterase, or Ca2+/CaM-dependent protein kinase II and to inhibit the CaM stimulation of these enzymes. The partial amino acid sequence of calvasculin revealed a high homology to the predicted protein derived from mRNA, named pEL-98, 18A2, 42A, or p9Ka. We also examined the physicochemical and biochemical properties of calvasculin. Using the antibody specific for calvasculin, we obtained evidence that calvasculin is present in abundance in bovine aorta but not in brain, lung, heart, or testis.
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PMID:Isolation and characterization of a calcium-binding protein derived from mRNA termed p9Ka, pEL-98, 18A2, or 42A by the newly synthesized vasorelaxant W-66 affinity chromatography. 173 18

We have found that a fungal strain, Talaromyces wortmannin KY12420, produces a potent inhibitor of smooth muscle myosin light chain kinase (MLCK). This active product, designated as MS-54, was isolated and purified from the culture broth of the fungus and identified as wortmannin. The inhibition of MLCK by wortmannin was prevented by a high concentration of ATP. The activity of the catalytic domain, which was disclosed by partial tryptic digestion, was also inhibited by wortmannin. These results suggest that wortmannin acts at or near to the catalytic site of the enzyme. It was shown clearly by kinetic analyses, preincubation studies, and dialysis experiments that the inhibitory action of wortmannin on MLCK was irreversible. Under the condition of preincubation for 3 min, 0.3 microM wortmannin inhibited the activity of MLCK, while 10 microM wortmannin had no effect on the activities of cAMP-dependent protein kinase, cGMP-dependent protein kinase, and calmodulin-dependent protein kinase II, and had little effect on protein kinase C activity. These data expressed clearly the marked selectivity of the compound for MLCK. Furthermore, wortmannin also inhibited both the phosphorylation of myosin light chain and the contraction in rat thoracic aorta stimulated with KCl, which indicates the effectiveness of the compound in the cellular level as an MLCK inhibitor.
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PMID:Wortmannin, a microbial product inhibitor of myosin light chain kinase. 173 24

Smooth muscle myosin light chain (LC) can be phosphorylated by myosin light chain kinase (MLCK) at Ser19 and Thr18 and by protein kinase C (PKC) at Thr9 and Ser1 or Ser2 under the in vitro assay conditions. Conversion of PKC to the spontaneously active protein kinase M (PKM) by proteolysis resulted in a change in the substrate specificity of the kinase. PKM phosphorylated both sets of sites in LC recognized by MLCK and PKC as analyzed by peptide mapping analysis. The PKM-catalyzed phosphorylation of these sites was not greatly affected by a MLCK inhibitor, ML-9, nor by the activators of MLCK, Ca2+ and calmodulin.
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PMID:Catalytic fragment of protein kinase C exhibits altered substrate specificity toward smooth muscle myosin light chain. 174 84

Avian myosin light chain kinase (MLCK) is inhibited by a range of plant-derived flavonoids. Maximal inhibition requires 2,3-unsaturation and polyhydroxylation of two of the three flavonoid rings. Phosphorylation of a synthetic myosin light chain-related peptide by wheat embryo Ca(2+)-dependent protein kinase (CDPK) is also inhibited by a range of flavonoids but phosphorylation of histone preparation III-S by wheat CDPK is not inhibited by flavonoids. The structural requirements for inhibition of wheat CDPK by flavonoids are more stringent than for inhibition of avian MLCK. Potent flavonoid inhibitors of wheat CDPK are unsaturated in 2,3 position, have hydroxyl groups in positions 3' and 4' and an additional hydroxyl in the chromone ring. Flavonoid glycosylation or methylation can abolish inhibition. A number of other naturally occurring plant phenolics including chalcones and gossypol also inhibit avian MLCK and wheat CDPK. Gossypol binds to calmodulin, abolishing Ca(2+)-dependent enhancement of dansyl-calmodulin fluorescence.
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PMID:Inhibition of wheat embryo calcium-dependent protein kinase and avian myosin light chain kinase by flavonoids and related compounds. 177 94

We studied the effects of various protein kinase inhibitors on the attachment of mouse lung carcinoma 3LL cells to the fibronectin (FN) substratum. Calmodulin antagonists (W-7 and W-13) and myosin light chain kinase inhibitors (ML-7 and ML-9) exhibited the inhibitory effect for the attachment, while inhibitors of protein kinases A and C were ineffective. Since Arg-Gly-Asp-containing hexapeptide blocked the attachment, cell surface FN receptor appeared to be involved in this mechanism. These results support the hypothesis that the cell attachment requires the rearrangement of the cytoskeleton in association with the phosphorylation of myosin light chain which would lead to the clustering of the cell surface FN receptors.
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PMID:Myosin light chain kinase inhibitors ML-7 and ML-9 inhibit mouse lung carcinoma cell attachment to the fibronectin substratum. 177 44

NPC 15437 inhibited protein kinase C (PKC) activity and [3H]phorbol 12,13-dibutyrate (PDBu) binding to the enzyme in a concentration-dependent manner (IC50 values, 19 +/- 2 microM and 23 +/- 4 microM, respectively). No inhibition of cAMP-dependent protein kinase A (PKA) or calcium/calmodulin-dependent myosin light chain kinase (MLCK) was observed. A detailed kinetic analysis of the interaction of NPC 15437 and a homogeneous preparation of PKC-alpha revealed a competitive type of inhibition with respect to activation of the enzyme by both phorbol 12-myristate 13-acetate (PMA) (Ki = 5 +/- 3 microM) and phosphatidylserine (PS) (Ki = 12 +/- 4 microM). Mixed inhibition (predominantly of the non-competitive type), with respect to activation of the enzyme by calcium, was also observed. These studies indicate that NPC 15437 is a selective inhibitor of PKC, interacting at the regulatory region of the molecule. NPC 15437 inhibited phorbol ester-induced ear edema in mouse (IC50 = 175 micrograms/ear) demonstrating the ability of NPC 15437 to inhibit PKC-mediated activity in intact cells.
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PMID:2,6-Diamino-N-([1-oxotridecyl)-2-piperidinyl]methyl)hexanamide (NPC 15437): a selective inhibitor of protein kinase C. 179 19

Purified myosin light chain kinase from smooth muscle is phosphorylated by cyclic AMP-dependent protein kinase, protein kinase C and the multifunctional calmodulin-dependent protein kinase II. Since phosphorylation in a specific site (site A) by any one of these kinases desensitizes myosin light chain kinase to activation by Ca2+/calmodulin, kinase phosphorylation could play an important role in regulating smooth muscle contractility. This possibility was investigated in 32P-labelled bovine tracheal smooth muscle. Treatment of tissues with carbachol, KCl, isoproterenol, or phorbol 12,13-dibutyrate increased the extent of kinase phosphorylation. Six primary phosphopeptides (A-F) of myosin light chain kinase were identified. Site A was phosphorylated to an appreciable extent only with carbachol or KCl, agents which contract tracheal smooth muscle. The extent of site A phosphorylation correlated to increases in the concentration of Ca2+/calmodulin required for activation. These results show that cyclic AMP-dependent protein kinase and protein kinase C do not affect smooth muscle contractility by phosphorylating site A in myosin light chain kinase. It is proposed that phosphorylation of myosin light chain kinase in site A, perhaps by calmodulin-dependent protein kinase II, may play a role in reported desensitization of contractile elements in smooth muscle to activation by Ca2+.
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PMID:Myosin light chain kinase phosphorylation: regulation of the Ca2+ sensitivity of contractile elements. 180 95

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 contractile state of smooth muscle is regulated primarily by the sarcoplasmic (cytosolic) free Ca2+ concentration. A variety of stimuli that induce smooth muscle contraction (e.g., membrane depolarization, alpha-adrenergic and muscarinic agonists) trigger an increase in sarcoplasmic free [Ca2+] from resting levels of 120-270 to 500-700 nM. At the elevated [Ca2+], Ca2+ binds to calmodulin, the ubiquitous and multifunctional Ca(2+)-binding protein. The interaction of Ca2+ with CaM induces a conformational change in the Ca(2+)-binding protein with exposure of a site(s) of interaction with target proteins, the most important of which in the context of smooth muscle contraction is the enzyme myosin light chain kinase. The interaction of calmodulin with myosin light chain kinase results in activation of the kinase that catalyzes phosphorylation of myosin at serine-19 of each of the two 20-kDa light chains (native myosin is a hexamer composed of two heavy chains (230 kDa each) and two pairs of light chains (one pair of 20 kDa each and the other pair of 17 kDa each)). This simple phosphorylation reaction triggers cycling of myosin cross-bridges along actin filaments and the development of force. Relaxation of the muscle follows removal of Ca2+ from the sarcoplasm, whereupon calmodulin dissociates from myosin light chain kinase regenerating the inactive kinase; myosin is dephosphorylated by myosin light chain phosphatase(s), whereupon it dissociates and remains detached from the actin filament and the muscle relaxes. A substantial body of evidence has been accumulated in support of this central role of myosin phosphorylation-dephosphorylation in the regulation of smooth muscle contraction. However, a wide range of physiological and biochemical studies supports the existence of additional, secondary Ca(2+)-dependent mechanisms that can modulate or fine-tune the contractile state of the smooth muscle cell. Three such mechanisms have emerged: (i) the actin-, tropomyosin-, and calmodulin-binding protein, calponin; (ii) the actin-, myosin-, tropomyosin-, and calmodulin-binding protein, caldesmon; and (iii) the Ca(2+)- and phospholipid-dependent protein kinase (protein kinase C).
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PMID:The Ayerst Award Lecture 1990. Calcium-dependent mechanisms of regulation of smooth muscle contraction. 181 84


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