Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.7.11.13 (protein kinase C)
 49,245 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The aim of the study was to investigate the effects of prolonged treatment with imipramine (10 mg kg-1/day i.p. for 21 days) on the translocation of protein kinase C (PKC) after stimulation of the alpha 1-adrenoceptor. Methoxamine (5-50 mg kg-1) and phenylephrine (0.1-1 mg kg-1) induced a rapid and long-term redistribution of PKC from the cytosolic to the membrane fraction in the rat frontal cortex and hippocampus. The effects of methoxamine and phenylephrine were completely blocked by pretreatment with prazosin. Prolonged pretreatment with imipramine changed the response of PKC to methoxamine and phenylephrine. Much lower doses of alpha 1-adrenoceptor agonists were able to induce the redistribution of PKC. Moreover, prolonged treatment with imipramine markedly increased the basal activity of PKC in the membrane fractions of the frontal cortex and hippocampus.
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PMID:The effect of prolonged imipramine treatment on the alpha 1-adrenoceptor-induced translocation of protein kinase C in the central nervous system in rats. 941 41

1. This study was designed to investigate the mechanism(s) of the negative inotropic effects of alpha1-adrenoceptor agonists observed in rat isolated left atria after exposure to free radicals. 2. Ouabain and calphostin C were used in contraction experiments to block the sodium pump and protein kinase C. Methoxamine-induced phospholipase C and Na+/K+ ATPase activities were measured. 3. Methoxamine (300 microM) increased contractile force by 1.6 +/- 0.2 mN in control atria but decreased contractile force in electrolysis-treated atria by 2.0 +/- 0.1 mN (P < 0.05), as determined 10 min after methoxamine addition. In contrast, the positive inotropic effects of endothelin-1 (30 nM) and isoprenaline (10 microM) were reduced from 2.6 +/- 0.3 to 1.3 +/- 0.1 mN and from 2.6 +/- 0.3 to 1.7 +/- 0.2 mN, respectively, by electrolysis treatment (P < 0.05), but not converted into a negative inotropic action. 4. In an inositol phosphate assay we observed that the stimulation of phospholipase C by methoxamine was attenuated by electrolysis when the (electrolyzed) medium from the organ bath was used, but the phospholipase C responses were restored by the use of fresh medium. However, fresh medium did not counteract the negative inotropic effect of methoxamine. Accordingly, the negative inotropic effect of methoxamine is not directly related to the impaired phospholipase C responses seen in atria subjected to electrolysis. 5. Ouabain (10 microM) and the protein kinase C inhibitor calphostin C (50 nM), completely prevented the negative inotropic effect of 300 microM methoxamine in electrolysis-treated atria. 6. Measurement of the Na+/K+ ATPase activity, revealed that in control atria, alpha1-adrenoceptor stimulation with 300 microM methoxamine, decreased the Na+/K+ ATPase activity by 14.4 +/- 7.7%. In contrast, methoxamine increased the Na+/K+ ATPase activity by 48.8 +/- 8.9% (P < 0.05) in electrolysis-treated atria. Interestingly, this increase in Na+/K+ ATPase activity was completely counteracted by calphostin C (1.4 +/- 0.1% over basal). 7. These results indicate that the negative inotropic effects of alpha1-adrenoceptor agonists, observed in rat isolated left atria exposed to free radicals, are likely to be caused by protein kinase C-mediated phosphorylation and subsequent activation of the Na+/K+ ATPase.
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PMID:Possible mechanism of the negative inotropic effect of alpha1-adrenoceptor agonists in rat isolated left atria after exposure to free radicals. 953 25

Cystic fibrosis (CF) airway epithelial cells have a reduced mass of ether-linked diacylglycerols which might alter protein kinase C (PKC)-regulated Cl secretion. PKC regulation of basolateral Na-K-2Cl cotransport (NKCC1) was investigated in CF nasal polyp epithelial cells and a CF/T43 cell line to ascertain whether PKC signaling was altered in CF. NKCC1 was detected as bumetanide-sensitive (86)Rb influx. Methoxamine, a alpha(1)-adrenergic agonist, increased PKC activity in cytosol and a particulate fraction for a prolonged time period, as predicted from previous studies on the generation of diglycerides induced with methoxamine. Short-term stimulation of CF/T43 cells for 40 s promoted a shift in PKC-delta and -zeta to a particulate fraction, increased activity of immune complexes of cytosolic PKC-delta and of particulate PKC-zeta and increased activity of NKCC1. Pretreatment with antisense oligonucleotide to PKC-delta blocked methoxamine-stimulated PKC-delta activity, reduced PKC-delta mass by 61.4%, and prevented methoxamine-stimulated activity of NKCC1. Sense and missense oligonucleotide to PKC-delta and antisense oligonucleotide to PKC-zeta did not alter expression of PKC-delta or the effects of methoxamine. These results demonstrate that PKC-delta-dependent activation of NKCC1 is preserved in CF cells and suggest that regulation of NKCC1 is independent of low ether-linked diglyceride mass.
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PMID:PKC signaling in CF/T43 cell line: regulation of NKCC1 by PKC-delta isotype. 1063 29

In an attempt to know the functional role of alpha1A-adrenoceptors in adipose tissue, white adipocytes (WAT) of Wistar rats were used to investigate the change of glucose uptake after pharmacological activation of alpha1-adrenoceptors. Methoxamine enhanced the uptake of radioactive glucose into isolated WAT in a concentration-dependent manner. Translocation of glucose transporter (GLUT4) from cytosol to membrane was also stimulated with methoxamine. Action of methoxamine to raise glucose uptake was abolished in WAT pre-incubated with the antagonists, both tamsulosin and WB 4101, at concentrations sufficient to block alpha1A-adrenoceptors. However, chlorethylclonidine (CEC). the antagonist of alpha1B-adrenoceptors, showed the inhibition of methoxamine-induced action only at a higher concentration. Even under the treatment with maximal concentration of CEC, methoxamine can produce action about 80% of the vehicle-treated control. The major role of alpha1A-adrenoceptors in the stimulation of glucose uptake by methoxamine can thus be considered. In the presence of specific inhibitor of phospholipase C (PLC), U73312, methoxamine-stimulated glucose uptake into WAT was reduced in a concentration-dependent manner and U73343, the negative control of U73312, did not affect the action of methoxamine. Moreover, chelerythrine and GF 109203X diminished the methoxamine-stimulated glucose uptake at a concentration sufficient to inhibit protein kinase C (PKC). Inhibition of phosphoinositide-3 kinase (PI-3 kinase) by LY294002 also abolished methoxamine-stimulated glucose uptake. Therefore. the obtained data suggest that an activation of alpha1A-adrenoceptors, presence in WAT, by agonist and/or neurotransmitter may increase the glucose uptake via PLC-PKC pathway and the activation of PI-3 kinase.
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PMID:Role of alpha1A-adrenoceptor in the regulation of glucose uptake into white adipocyte of rats in vitro. 1111 46

The effects of alpha-adrenergic receptor (alpha-AR) stimulation alone and the effects in the presence of beta-adrenergic receptor (beta-AR) stimulation were examined on L-type Ca(2+) currents (I(Ca-L)) in the absence and presence of hypoxia. The alpha-AR agonist methoxamine either had no effect or had a slight inhibitory effect on basal I(Ca-L) in the absence and presence of hypoxia. Hypoxia significantly decreased the K(0.5) for activation of I(Ca-L) by norepinephrine from 79.8+/-6.6 to 13.3+/-0.7 nmol/L. To determine whether hypoxia specifically altered the sensitivity of the channel to alpha-AR stimulation, cells were exposed to increasing concentrations of methoxamine in the presence of 100 nmol/L isoproterenol (Iso). In the absence of hypoxia, methoxamine inhibited the Iso-activated I(Ca-L) in a concentration-dependent manner with an EC(50) of 86.9+/-9.9 micromol/L. However, in the presence of hypoxia, the EC(50) for inhibition of I(Ca-L) by methoxamine was significantly increased to 266.7+/-10.8 micromol/L. Methoxamine had little effect on I(Ca-L) activated by forskolin or histamine in the absence or presence of hypoxia. In addition, inhibition of protein kinase C by bisindolylmaleimide 1 or protein kinase C beta peptide inhibitor had no effect on the methoxamine-induced antagonism of I(Ca-L) in the absence or presence of hypoxia. The tyrosine kinase inhibitor genistein attenuated the methoxamine response in nonhypoxic cells only. However, during hypoxia it was attenuated with the phospholipase A(2) inhibitors mepacrine and indomethacin. These findings represent a novel regulation of the L-type Ca(2+) channel by the phospholipase A(2) pathway and illustrate the complexity of regulation of the channel under hypoxic conditions.
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PMID:Hypoxia alters the sensitivity of the L-type Ca(2+) channel to alpha-adrenergic receptor stimulation in the presence of beta-adrenergic receptor stimulation. 1137 73


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