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

1. Small strips from third-order branches of rabbit mesenteric artery (approximately 150-200 microM wide) contracted in response to noradrenaline (10 microM) or 5-hydroxytryptamine (5-HT; 10 microM) in oxygenated Krebs solution containing 2.5 mM Ca2+. In a Ca(2+)-free mock intracellular solution (0 Ca2+ plus 0.2 mM EGTA), noradrenaline (10 microM) and caffeine (10 mM) induced only a single, transient contraction in artery strips, while 5-HT (10 microM) failed to induce any response. 2. In strips of mesenteric artery which had been permeabilized with Staphylococcus alpha-toxin and bathed in Ca(2+)-free mock intracellular solution, noradrenaline (10 microM), caffeine (10 mM) and D-myo-inositol (1,4,5)-trisphosphate (IP3, 100 microM), but not 5-HT (10 or 100 microM) induced a transient contraction. In contrast to the non-permeabilized strips, contractions to noradrenaline, caffeine and IP3 were restored by prior incubation (10 min) in solution containing 0.08 microM Ca2+. The contractions to noradrenaline and IP3 in permeabilized muscle strips required the presence of 100 microM guanosine 5'-triphosphate (GTP), although in the absence of Ca2+. GTP alone did not induce contraction. 3. Exposure of permeabilized mesenteric artery strips to IP3 significantly reduced the subsequent contractile responses to caffeine. Contractile responses to caffeine and IP3 were abolished by the Ca(2+)-ATPase inhibitor, thapsigargin (1 microM). 4. Ca2+ (0.1-10 microM) induced concentration-dependent contraction in permeabilized artery strips. In strips which were submaximally contracted with 0.5 microM Ca2+/100 microM GTP, the subsequent addition of 5-HT (10 microM) stimulated further contraction. The protein kinase C inhibitor, H-7 (1 microM) abolished the 5-HT/GTP-induced contraction, but did not alter the contraction to Ca2+. 5. In non-permeabilized, endothelium-denuded segments of rabbit mesenteric artery bathed in Ca2+-replete Krebs solution, noradrenaline (10 microM) stimulated a rapid, transient accumulation of IP3. 5-HT(100 microM) failed to stimulate IP3 accumulation during exposure periods of up to 5 min. 5-HT (100 microM)did stimulate IP3 accumulation if the external K+ concentration was raised (to around 25 mM). This concentration of K+ alone did not stimulate IP3 production and the 5-HT-stimulated IP3 accumulation in the presence of elevated extracellular [K+] was abolished by the alpha l-adrenoceptor antagonist, prazosin(O.1 microM).6. These results suggest that intracellular Ca2+ release does not play an important role in 5-HT-induced smooth muscle contraction in the rabbit mesenteric artery. This is despite the fact that a significant intracellular Ca2+ pool is present in these cells, which can be discharged by either noradrenaline or IP3.However, 5-HT did stimulate smooth muscle contraction in the presence of raised intracellular calcium,suggesting that a component of the contraction to 5-HT will reflect an increase in myofilament Ca2+sensitivity, possibly due to the activation of protein kinase C.
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PMID:Importance of inositol (1,4,5)-trisphosphate, intracellular Ca2+ release and myofilament Ca2+ sensitization in 5-hydroxytryptamine-evoked contraction of rabbit mesenteric artery. 800 97

Previous studies have demonstrated that receptor-mediated vasoconstriction is impaired in chronic portal hypertension (PH). Furthermore, it has been suggested that altered vasoconstrictor effectiveness in chronic PH is due to a defect in the intracellular events associated with smooth muscle activation and not to impaired coupling of vasoconstrictors with vascular smooth muscle receptors. The present study was designed to determine whether nonreceptor-mediated vasoconstrictor responses are impaired in the PH intestinal microcirculation. Specifically, we examined the effects of aluminum fluoride-induced activation of G proteins, KCl-induced depolarization, caffeine-induced release of intracellular Ca2+, and l-indolactam-induced activation of protein kinase C on the intestinal microcirculation of normal (Norm, n = 39) and PH (n = 42) rats. The small intestine was prepared for microcirculatory studies and transferred to a video microscope. First-order arteriolar (1A) diameter and red cell velocity were measured on-line. Blood flow was calculated from the product of velocity and microvessel cross-sectional area. After a control period, the microvasculature was exposed to a solution containing aluminum chloride plus sodium fluoride, potassium chloride, caffeine, or l-indolactam. Maximal decreases in arteriolar diameter produced by aluminum fluoride, KCl, caffeine, and l-indolactam were significantly greater in Norm rats when compared with PH rats. Changes in arteriolar blood flow were also larger in Norm than in PH rats. The results of the present study provide the first direct evidence of an impaired response to second-messenger activation in the PH circulation.
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PMID:Nonreceptor-mediated intestinal vasoconstriction in portal hypertensive rats. 804 3

1. The release of creatine kinase (CK) in the Langendorff-perfused rat heart during the Ca(2+)-paradox, was critically dependent on the duration and [Ca2+]o of the initial Ca(2+)-depletion phase. 2. When [Ca2+]i was raised by perfusion with caffeine or under N2, activation of the protein kinase C pathway (PKC) produced a small but significant release of CK. PKC stimulation is therefore able to substitute for the Cao(2+)-depletion of the Ca(2+)-paradox. 3. The PKC inhibitor, 1-(5-isoquinolinyl sulphonyl)-2-methyl piperazine, (2 x 10(-6) M) inhibited both the Ca(2+)-paradox and caffeine-induced release of CK. 4. It is concluded that the PKC pathway has a regulatory role for the damage system of the sarcolemma that is responsible for the release of cytosolic proteins.
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PMID:Does the protein kinase C pathway modulate sarcolemma damage and the release of cytosolic proteins in the rat heart? 810 Nov 61

1. Membrane currents activated by thyrotrophin-releasing hormone (TRH) were investigated in the dissociated rat hippocampal CA1 pyramidal neurone using the nystatin perforated patch recording configuration. 2. Under current-clamp condition, TRH caused a transient hyperpolarization accompanied by a decrease of firing activity and a successive long-lasting depolarization. The latter induced a blockade of firing. 3. When neurones were held at a holding potential (VH) of -40 mV under voltage clamp, TRH elicited a transient outward current with an increase in the membrane conductance, which was followed by a sustained inward current with a decrease in membrane conductance. The inactive TRH metabolite, TRH free acid, did not induce any currents. 4. The reversal potential of TRH-induced outward current (ETRH) was close to the K+ equilibrium potential (EK). The change in ETRH for a 10-fold change in extracellular K+ concentration was 56.4 mV, indicating that the membrane behaves like a K+ electrode in the presence of TRH. On the other hand, the TRH-induced inward current was due to suppression of a slow inward current relaxation during hyperpolarizing voltage commands to -50 mV from a VH of -40 mV, indicating the suppression of the voltage- and time-dependent component of the K+ current (M-current). 5. The TRH-induced outward current (ITRH) increased in a concentration-dependent manner over the concentration range 10(-8)-10(-6) M. The half-maximum concentration was 7.4 x 10(-8) M and the Hill coefficient was 1.5. 6. The TRH-induced outward current (ITRH) was antagonized by K+ channel blockers such as tetraethylammonium (TEA), 4-aminopyridine (4-AP) and Ba2+ in a concentration-dependent manner. ITRH was insensitive to both apamin and iberiotoxin. 7. The first application of TRH to neurones perfused with Ca(2+)-free external solution containing 2 mM EGTA could induce ITRH but the TRH response diminished dramatically with successive applications. Intracellular perfusion with a Ca2+ chelator, 1,2-bis(O-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid (BAPTA), also diminished the TRH response. 8. The depletion of Ca2+ from the intracellular Ca2+ store by thapsigargin blocked the TRH response without affecting the caffeine response. Pretreatment with Li+ significantly enhanced ITRH, suggesting that ITRH is involved in the elevation of intracellular free Ca2+ released from the inositol 1,4,5-trisphosphate (IP3)-sensitive Ca2+ store site but not from the caffeine-sensitive one. 9. Staurosporine, a protein kinase C (PKC) inhibitor, suppressed ITRH in a concentration-dependent manner (the half-maximum inhibitory concentration (IC50), was 2.45 x 10(-8) M).(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Potassium currents operated by thyrotrophin-releasing hormone in dissociated CA1 pyramidal neurones of rat hippocampus. 814 66

Amyloid beta peptide (A beta) is released into the media of a variety of cells in culture during normal metabolism. The discovery of several missense mutations within or flanking the A beta region of the beta amyloid precursor protein (beta APP) in familial Alzheimer's disease provides strong evidence for a role of altered processing of beta APP in the pathogenesis of this disorder. The cellular mechanisms that regulate the relative utilization of the secretory pathway, which causes beta APP to be cleaved within the A beta domain, and the alternative proteolytic pathway, which produces intact A beta, are unknown. It is hypothesized that a number of neurodegenerative diseases, including Alzheimer's disease, are characterized by abnormal calcium metabolism. We investigated the effect of disordered calcium homeostasis on A beta production in human kidney 293 cells transfected with beta APP cDNA. A beta immunoprecipitated from the conditioned media of cells was compared to immunoprecipitated full-length and secreted forms of beta APP in both metabolic labeling and pulse-chase labeling paradigms. The calcium ionophore A23187 consistently increased the production of A beta approximately 3-fold. This effect was dependent on the presence of extracellular calcium in intact cells. Caffeine also increased A beta production, possibly through release of calcium from intracellular stores. The increase in A beta was cAMP-independent, and it was not mediated by a protein kinase C-dependent pathway, as treatment with phorbol esters decreased A beta levels. The effects of the ionophore on beta APP maturation and phosphorylation were also established. We conclude that elevation of intracellular calcium levels has an important effect on beta APP maturation and proteolytic processing and substantially enhances the production and release of the amyloidogenic A beta peptide.
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PMID:Calcium ionophore increases amyloid beta peptide production by cultured cells. 816 10

Changes in cytoplasmic free Ca2+ concentration, [Ca]i, elicited by ATP, were studied in neurones cultured from rat hippocampus and thalamus. ATP evoked [Ca]i increases in about 30% of all cells tested and suppressed [Ca]i transients in responsive cells. The number of responses to ATP markedly increased after pretreatment of cells with inhibitors of protein kinase C, H-7 or staurosporine. The potentiation was blocked by a phorbol ester and by dioleylglycerol. In pretreated cells both once peak [Ca]i and the number of successive trials were augmented by an [ATP] increase. The former effect can be described by the Michaelis-Menten equation whereas the latter one has a steeper, leftward-shifted dependence. Both concentration dependences are explained with a model, describing Ca2+ release as a threshold phenomena. ATP analogues had the rank of potency: ATP approximately ADP >> AMP > alpha, beta-MeATP. A single ATP application depleted internal Ca2+ stores which could be replenished by brief membrane depolarization with high-K+. ATP- and caffeine-induced [Ca]i transients were independent, indicating two non-overlapping Ca2+ storage sites. Only caffeine effects were potentiated at an elevated [Ca]i level, showing a Ca(2+)-induced Ca2+ release. Inhibitors of the Ca2+ pump in internal stores, ryanodine and sulphydryl reagents suppressed the ATP-induced [Ca]i transients, acting via different mechanisms.
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PMID:Metabotropic ATP receptor in hippocampal and thalamic neurones: pharmacology and modulation of Ca2+ mobilizing mechanisms. 818 32

1. The effects of 12-O-tetradecanoyl 4 beta-phorbol 13-acetate (beta-TPA) on the inositol 1,4,5-trisphosphate (IP3) production, Ca2+ release from the intracellular Ca2+ stores and sensitization of contractile apparatus, induced by prostaglandin F2 alpha (PGF2 alpha) and U46619, a thromboxane A2-mimetic, were studied, using fura-2-loaded and -unloaded rat thoracic aortic strips. 2. Both eicosanoids had characteristic patterns of responses in Ca(2+)-free, 2 mM EGTA-containing solution (Ca(2+)-free solution). They induced transient increases in intracellular Ca2+ concentration ([Ca2+]i) without corresponding transient contraction, but produced delayed, sustained contraction, where [Ca2+]i was returned to the basal level. 3. Treatment with beta-TPA for 60 min reduced the eicosanoids-induced IP3 production, suggesting that the treatment inhibits PIP2 breakdown. 4. The treatment also attenuated [Ca2+]i transient induced by the eicosanoids, but not by caffeine (an IP3-independent releaser of stored Ca2+), in fura-2-loaded preparations incubated in Ca(2+)-free solution. 5. In contrast in the presence of beta-TPA, the sustained contractions evoked by the eicosanoids in Ca(2+)-free solution were potentiated, suggesting that the sites of actions of beta-TPA and the eicosanoids may differ from each other. 6. PGF2 alpha and U46619 utilize different and parallel signal transduction pathways to release Ca2+ by IP3 produced by PIP2 breakdown (beta-TPA-sensitive), and to increase the sensitivity of contractile apparatus, in which protein kinase C may not be involved (beta-TPA-insensitive).
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PMID:Eicosanoid-induced Ca2+ release and sustained contraction in Ca(2+)-free media are mediated by different signal transduction pathways in rat aorta. 824 63

The protein kinase inhibitor 2-aminopurine (2-AP) greatly stimulated expression in human promonocytes-macrophages of plasmid constructs carrying various reporter genes (chloramphenicol acetyltransferase, lacZ, firefly luciferase [luc], and Salmonella typhimurium histidinol dehydrogenase [his]) driven by the human immunodeficiency virus type 1 (HIV-1) long terminal repeat. Adenine, adenosine, and caffeine were also effective inducers, but other purine or pyrimidine derivatives were ineffective. Experiments with mutant derivatives of the HIV-1 long terminal repeat revealed no specific eukaryotic promoter elements necessary for 2-AP induction but indicated the need for some minimum combination of such elements. Induction of HIV-1-directed gene expression appeared not to require action of the transcription factor NF-kappa B. The mechanism of induction was investigated by using the luc and his genes linked to the HIV-1 long terminal repeat. 2-AP induced marked, steady rises in mRNA accumulation from both transfected and chromosomally integrated HIV-1 constructs but no increases from an endogenous gene encoding gamma-actin or glucose 6-phosphate dehydrogenase. Thus, induction is selective and not an artifact induced by transfecting DNA into cells. In run-on transcription experiments, the rates of transcription initiation of both transfected and integrated copies of the his gene increased about sixfold in cells treated with 2-AP. Thus, while increased initiation accounted for a portion of 2-AP induction, it could not cause the far greater increase in steady-state mRNA levels. 2-AP induction did not change mRNA decay rates and differed from the phorbol ester (phorbol myristate acetate)-induced activation of the protein kinase C-NF-kappa B pathway in its time course and in its requirement for new protein synthesis. Gel retardation assays showed that unlike phorbol myristate acetate induction, 2-AP induction is enhancer independent. Whereas many previous studies have implicated the activation of various protein kinases in gene induction, we here describe a mechanism of gene activation that appears to involve protein kinase inhibition as a component of the induction response.
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PMID:Inducible transcriptional activation of the human immunodeficiency virus long terminal repeat by protein kinase inhibitors. 835 80

Receptors for the peptidyl leukotrienes, (LT)C4, LTD4 and LTE4, and the signaling pathways to which they are coupled were characterized in isolated guinea pig gastric muscle cells. The three LTs were equipotent contractile agonists (EC50 values = 0.10-0.12 nM), but they elicited their responses by interacting with distinct receptors. The contractile responses to LTD4 and LTE4, but not LTC4, were inhibited by the LTD4 antagonist, SKF 104353 [2-(S)-hydroxy-3-(R)-[(2-carboxyethyl)thiol]-3-[2-(8- phenyloctyl)phenyl]-propanoic acid]. Similar Ki estimates for SKF 104353 suggested interaction of LTD4 and LTE4 with a common receptor. Decisive evidence for distinct LTC4 and LTD4/LTE4 receptors was obtained by applying a receptor protection technique. Cells in which LTC4 was used as a receptor protective agent while other receptors were inactivated by N-ethylmaleimide retained their responses to LTC4 only. Cells in which LTD4, LTE4 or SKF 104353 were used as a receptor protective agent retained their responses to LTD4 and LTE4 only. Both LTC4 and LTD4/LTE4 receptors were coupled to Pl hydrolysis: all three LTs stimulated similar increases in inositol 1,4,5-trisphosphate (IP3) levels (3.9-4.3 pmol/10(6) cells), protein kinase C activity (85-94 pmol/mg/min) and cytosolic-free Ca++ ([Ca++]i) (278-306 nM). Contractile responses were abolished: 1) when Pl hydrolysis was inhibited by neomycin and 2) when Ca++ stores were depleted by pretreatment of muscle cells with caffeine in Ca(++)-free medium, but not when muscle cells were incubated in Ca(++)-free medium or with Ca++ channel blockers, suggesting that contraction and [Ca++]i were mediated by IP3-dependent Ca++ release.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Characterization of distinct receptors for the peptidyl leukotrienes LTC4 and LTD4/LTE4 coupled to the same signaling pathway in isolated gastric muscle cells. 839 21

It is believed that inotropic agents exert their effects in cardiac muscle via a modulation of Ca2+ cycling; however, the involvement of phospholipase activation and the biochemical pathways participating in inotropic responsiveness remain unclear. The aim of the current study was to determine whether arachidonic acid and/or eicosanoids participate in inotropic responses by modulating Ca2+ cycling in cardiac myocytes. Experiments were performed with populations of freshly isolated, fura-2-loaded adult rat ventricular myocytes. Arachidonic acid stimulated a transient increase in cytosolic free Ca2+, which was still present after addition of EGTA but was significantly reduced by pretreatment with caffeine. Addition of arachidonic acid to either electrically stimulated or quiescent myocytes enhanced the amplitude of the ATP-induced Ca2+ transient. This effect was still observed in the presence of inhibitors of cyclooxygenase, lipoxygenase, and epoxygenase pathways but was significantly diminished after pretreatment with inhibitors of protein kinase C. In contrast, arachidonic acid attenuated the amplitude of electrically induced Ca2+ transients. This effect was mimicked by eicosatetraynoic acid and by the K+ channel agonist pinacidil. The inhibitory effect of eicosatetraynoic acid and arachidonic acid was reversed by addition of fatty acid-free bovine serum albumin. Together, these results suggest that arachidonic acid may play a physiological role in cardiac muscle excitation-contraction coupling as a modulator of sarcolemmal ion channels and/or Ca2+ release from the sarcoplasmic reticulum.
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PMID:Modulation of Ca2+ cycling in cardiac myocytes by arachidonic acid. 841 90


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