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

The molecular mechanisms for regulating water balance in many tissues are unknown. Like the kidney, the eye contains multiple water channel proteins (aquaporins) that transport water through membranes, including two (AQP1 and AQP4) in the ciliary body, the site of aqueous humor production. Previous results from our laboratory demonstrated that water channel activity of AQP1 was significantly increased by protein kinase A (PKA) activators such as cyclic-AMP (cAMP) and forskolin. The purpose of this study is to determine whether PKA-dependent protein phosphorylation is involved in the regulation of water channel activity of AQP1. Results presented here suggest that catalytic subunit of protein kinase A significantly increased the amount of phosphorylated AQP1 protein. In addition, these results indicated that cAMP-responsive redistribution of AQP1 may be regulated by phosphorylation of AQP1. Moreover, they provide new insights on the molecular mechanisms for regulating water balance in several tissues involving rapid water transport such as ciliary epithelium. In addition, they suggest important potential roles for AQP1 in several clinical disorders involving rapid water transport such as glaucoma.
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PMID:Protein kinase A-dependent phosphorylation of aquaporin-1. 1087 6

To study whether nipradilol, which is used as an ophthalmic solution for the treatment of glaucoma, has a cytoprotective effect, we investigated its effect on the apoptosis induced by serum withdrawal in PC12 cells. Nipradilol has alpha1- and beta-adrenoceptor-blocking and nitric oxide (NO)-donating properties. We also investigated the effects of timolol, prazosin and S-nitroso-N-acetylpenicillamine (SNAP) on PC12 cell death. Serum withdrawal from PC12 cells resulted in apoptosis, and the survival rate was decreased in a time-dependent manner. The addition of nipradilol to the medium showed a cytoprotective effect on PC12 cell death in a dose-dependent manner, but timolol and prazosin did not. We measured caspase-3 activity to clarify the mechanism of the inhibition of apoptosis in the presence or absence of dithiothreitol (DTT). The caspase-3 activity could be reactivated by DTT. In addition, to investigate the relationship of the cGMP-dependent pathway to the nipradilol-induced cytoprotective effect, we tested the effect of the protein kinase G inhibitor KT5823. KT5823 partially reversed the nipradilol-mediated cytoprotective effect. These results indicate that the cytoprotective effect of nipradilol in PC12 cell death was due to the caspase-3 inhibition mediated by NO-related S-nitrosylation and activation of protein kinase G.
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PMID:Nipradilol inhibits apoptosis by preventing the activation of caspase-3 via S-nitrosylation and the cGMP-dependent pathway. 1235 66

Application of NMDA induces a depolarization and increase of intracellular calcium concentration ([Ca2+]i) in retinal ganglion cells, which cause ganglion cell death in models of glaucoma. In the present study, we investigated the pharmacological mechanism of how NMDA-evoked increase in calcium could be modulated in dissociated retinal ganglion cells from tiger salamander. In these neurons, protein kinase A (PKA) up-regulated the NMDA-evoked [Ca2+]i increase. In the presence of 8-bromo-cAMP or forskolin to stimulate PKA, the elevation level of [Ca2+]i induced by NMDA became even higher; in the presence of H-89, a PKA inhibitor, the NMDA-evoked [Ca2+]i increase was attenuated. In addition, applications of adrenergic compounds were also found to influence the NMDA-evoked [Ca2+]i increase. UK-14,304, a selective alpha2 agonist, reduced the elevation level of [Ca2+]i caused by NMDA. In contrast, isoproterenol, a beta agonist, augmented the NMDA-evoked [Ca2+]i increase. These adrenergic regulations were due to direct activation of adrenoceptors, since modulations of both UK-14,304 and isoproterenol on the NMDA-evoked [Ca2+]i increase were abolished by their respective antagonists. Furthermore, adrenergic regulations were mediated through a PKA-related pathway since PKA inhibitor blocked adrenergic regulations. The possible modulatory site(s) by PKA was also discussed.
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PMID:NMDA-evoked [Ca2+]i increase in salamander retinal ganglion cells: modulation by PKA and adrenergic receptors. 1239 74

Cyclic nucleotides acting through their associated protein kinases, the cGMP- and cAMP-dependent protein kinases, can relax smooth muscles without a change in free intracellular calcium concentration ([Ca2+]i), a phenomenon referred to as Ca2+ desensitization. The molecular mechanisms by which these kinases bring about Ca2+ desensitization are unknown and an understanding of this phenomenon may lead to better therapies for treating diseases involving defects in the contractile response of smooth muscles such as hypertension, bronchospasm, sexual dysfunction, gastrointestinal disorders and glaucoma. Utilizing a combination of real-time proteomics and smooth muscle physiology, we characterized a distinct subset of protein targets for cGMP-dependent protein kinase in smooth muscle. Among those phosphoproteins identified was calponin homology-associated smooth muscle (CHASM), a novel protein that contains a calponin homology domain and shares sequence similarity with the smoothelin family of smooth muscle specific proteins. Recombinant CHASM was found to evoke relaxation in a concentration dependent manner when added to permeabilized smooth muscle. A co-sedimentation assay with actin demonstrated that CHASM does not possess actin binding activity. Our findings indicate that CHASM is a novel member of the smoothelin protein family that elicits Ca2+ desensitization in smooth muscle.
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PMID:Modulation of smooth muscle contractility by CHASM, a novel member of the smoothelin family of proteins. 1532 99

Prostaglandins (PGs) have been implicated in lowering intraocular pressure (IOP). A possible role of cyclooxygenase-2 (COX-2) in this process was emphasized by findings showing impaired COX-2 expression in the non-pigmented ciliary epithelium (NPE) of patients with primary open-angle glaucoma. The present study investigates the effect of the major COX-2 product, PGE(2), on the expression of its synthesizing enzyme in human NPE cells (ODM-2). PGE(2) led to an increase of COX-2 mRNA and protein expression, whereas the expression of COX-1 remained unchanged. Upregulation of COX-2 expression by PGE(2) was accompanied by time-dependent phosphorylations of p38 mitogen-activated protein kinase (MAPK) and p42/44 MAPK, and was abrogated by inhibitors of both pathways. Moreover, PGE(2)-induced COX-2 expression was suppressed by the intracellular calcium chelator, BAPTA/AM, and the protein kinase C inhibitor bisindolylmaleimide II, whereas the protein kinase A inhibitor H-89 was inactive in this respect. Induction of COX-2 expression was also elicited by butaprost (EP(2) receptor agonist) and 11-deoxy PGE(1) (EP(2)/EP(4) receptor agonist), but not by EP(1)/EP(3) receptor agonists (17-phenyl-omega-trinor PGE(2), sulprostone). Consistent with these findings, the EP(1)/EP(2) receptor antagonist, AH-6809, and the selective EP(4) receptor antagonist, ONO-AE3-208, significantly reduced PGE(2)-induced COX-2 expression. Collectively, our results demonstrate that PGE(2) at physiologically relevant concentrations induces COX-2 expression in human NPE cells via activation of EP(2)- and EP(4) receptors and phosphorylation of p38 and p42/44 MAPKs. Positive feedback regulation of COX-2 may contribute to the production of outflow-facilitating PGs and consequently to regulation of IOP.
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PMID:Prostaglandin E2 induces cyclooxygenase-2 expression in human non-pigmented ciliary epithelial cells through activation of p38 and p42/44 mitogen-activated protein kinases. 1625 48

A number of genes associated with life phenomena have been identified by the achievement of genome projects. As both comprehensive analysis and methods for investigation of specific genes have been developed, we can understand the pathogenesis of ocular diseases and develop novel medical treatments based upon detailed information on molecular mechanisms. In our review article, we focused on three vision-threatening ocular diseases; glaucoma, age-related macular degeneration (AMD) and proliferative vitreoretinopathy (PVR), and discussed the potential and problems related to retinal regenerative therapy. Regarding glaucoma, we investigated the relationships between aqueous humor and cell components in the aqueous outflow route. We have revealed that the Rho-Rho-associated coiled-coil-forming protein kinase (ROCK) signal transduction pathway participates in regulation of the aqueous outflow route, and that ROCK inhibitors and several protein kinase inhibitors exert intraocular pressure-lowering effects. Also, we conducted a series of investigations on familial amyloidotic polyneuropathy (FAP), as a representative secondary glaucoma caused by genetic mutations in a single gene. We reviewed the clinical features of ocular complications derived from FAP, their molecular mechanisms and possibilities for the development of novel medical treatments. In addition, we discussed a novel therapeutic concept, "neuroprotection", and showed the potential of some drugs as candidates for the neuroprotective treatment of glaucoma. Against AMD, we have performed a series of experiments from the viewpoint of similarity with atherosclerotic lesions. We have shown the molecular mechanisms of AMD associated with up-regulated expression of scavenger receptors and the interaction between leukocytes and vascular endothelial cells. Furthermore, in the pathogenesis of PVR, we described the role of epithelial-mesenchymal transition in retinal pigment epithelial cells and demonstrated the usefulness of enzymatic vitrectomy. Although retinal regenerative therapy has attracted much attention from global investigators, we pointed out its limitation for clinical application, and developed researches on efficient culture method using physiologically active factors for proliferating retinal stem cells with multi-potentiality, differentiation of the transplanted progenitor cells, and axon guidance of neurons by extracellular matrices.
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PMID:[New understanding and development of medical treatments for ocular diseases based upon molecular mechanisms]. 1640 90

Alzheimer's disease (AD) is an age-related neurodegenerative disease. There are increasing lines of evidence showing that the molecular signaling pathways in aged cells are altered so that cells are susceptible to injury. We and other laboratories have demonstrated the significant involvement of double-stranded RNA-dependent protein kinase (PKR) in beta-amyloid (A beta) peptide neurotoxicity and in AD. Fructus lycii (the fruit of Lycium barbarum) has long been used in oriental medicine as an anti-aging agent. Our previous studies demonstrated that the aqueous extract isolated from L. barbarum exhibited significant protection on cultured neurons against harmful chemical toxins such as A beta and dithiothreitol. We also showed that the polysaccharide-containing extract (LBP) from L. barbarum exhibited neuroprotective effects in the retina against ocular hypertension in a laser-induced glaucoma animal model. In this study, we aimed to investigate whether LBP can elicit neuroprotection to neurons stressed by A beta peptides. Furthermore, we planned to isolate and identify the neuroprotective agent from LBP using chromatographic methods. Our results showed that pretreatment of LBP effectively protected neurons against A beta-induced apoptosis by reducing the activity of both caspase-3 and -2, but not caspase-8 and -9. A new arabinogalactan-protein (LBP-III) was isolated from LBP and attenuated A beta peptide-activated caspase-3-like activity. LBP-III markedly reduced the phosphorylation of PKR triggered by A beta peptide. Since the phosphorylation state of PKR increased with age, reduction of its phosphorylation triggered by A beta peptide may implicate that LBP-III from Fructus lycii is a potential neuroprotective agent in AD. As herbal medicine has received increasing attention for the treatment of AD, our study will open a window for the development of a neuroprotective agent for anti-aging from Chinese medicine.
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PMID:Characterization of the effects of anti-aging medicine Fructus lycii on beta-amyloid peptide neurotoxicity. 1761 46

Myocilin is a gene linked to the most common form of glaucoma, a major blinding disease. The trabecular meshwork (TM), a specialized eye tissue, is believed to be involved, at least in part, in the development of glaucoma. The myocilin expression is known to be up-regulated by glucocorticoids in TM cells, and an altered myocilin level may be the culprit in conditions such as corticosteroid glaucoma. Wild type myocilin, when transfected into cultured human TM cells, induced a dramatic loss of actin stress fibers and focal adhesions. Myocilin transfectants displayed a heightened sensitivity to trypsin. Adhesion to fibronectin, collagens, and vitronectin was compromised. The fibronectin deposition and the levels of fibronectin protein and mRNA were also reduced in myocilin transfectants. The fibronectin deposition could be restored by treatment with lysophosphatidic acid, a Rho stimulator. Assays further revealed that upon myocilin overexpression, the activity of RhoA was diminished, whereas the cAMP level and the protein kinase A (PKA) activity were augmented. Myocilin protein did not affect actin polymerization. The collapse of actin stress fibers and increased trypsin sensitivity from myocilin transfection could be reverted by co-expression of constitutively active RhoA or by treatment with PKA inhibitor H-89. The PKA activity, however, was not modified by co-expression of either constitutively active or dominant negative RhoA. These results demonstrate that myocilin has a de-adhesive activity and triggers signaling events. cAMP/PKA activation and the downstream Rho inhibition are possible mechanisms by which myocilin in overabundance may lead to TM cell or tissue damage.
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PMID:Rho GTPase and cAMP/protein kinase A signaling mediates myocilin-induced alterations in cultured human trabecular meshwork cells. 1798 96

Rho kinase (ROCK) is an attractive therapeutic target for various diseases including glaucoma, hypertension, and spinal cord injury. Herein, we report the development of a series of ROCK-II inhibitors based on 4-quinazolinone and quinazoline scaffolds. SAR studies at three positions of the quinazoline core led to the identification of analogs with high potency against ROCK-II and good selectivity over protein kinase A (PKA).
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PMID:Synthesis and biological evaluation of 4-quinazolinones as Rho kinase inhibitors. 2134 13

Rho kinase (ROCK) inhibitors are potential therapeutic agents to treat disorders such as hypertension, multiple sclerosis, cancers, and glaucoma. Here, we disclose the synthesis, optimization, biological evaluation of potent indole and 7-azaindole based ROCK inhibitors that have high potency on ROCK (IC(50)=1 nM) with 740-fold selectivity over PKA (47). Moreover, 47 showed very good DMPK properties making it a good candidate for further development. Finally, docking studies with a homology model of ROCK-II were performed to rationalize the binding mode of these compounds and showed the compounds bound in both orientations to take advantage to H-bonds with Lys-121 of ROCK-II.
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PMID:Discovery and optimization of indoles and 7-azaindoles as Rho kinase (ROCK) inhibitors (part-I). 2200 18


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