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)

Employing the non-recirculating perfused rat liver preparation, we have investigated the regulation of hepatic gluconeogenesis, and metabolic fluxes through the tricarboxylic acid cycle and 2-oxoglutarate dehydrogenase reaction by epidermal growth factor (EGF) which mimics the actions of both insulin and Ca(2+)-mobilizing hormones (e.g. vasopressin). As monitored by the rate of 14CO2 production from [2-14C]pyruvate (0.5 mM), EGF (10 nM) transiently stimulated the activity of the tricarboxylic acid cycle. EGF also transiently stimulated hepatic gluconeogenesis from pyruvate. The transient stimulation of tricarboxylic acid cycle activity and gluconeogenesis were accompanied by an increase in perfusate Ca2+ content indicating that EGF also altered hepatic Ca2+ fluxes. EGF-elicited stimulation of gluconeogenesis was, at least in part, the result of a transient (50%) inhibition of pyruvate kinase activity. Likewise, EGF-mediated stimulation of tricarboxylic acid cycle activity can, in part, be attributed to EGF-elicited stimulation of metabolic flux through the mitochondrial, Ca(2+)-sensitive, 2-oxoglutarate dehydrogenase reaction. The regulation of hepatic metabolism by EGF appears to be the manifestation of alteration in cellular Ca2+ content since in experiments performed under conditions known to abolish the ability of EGF to alter cytosolic free-Ca2+ concentrations, i.e. in livers of pertussis-toxin-treated rats, EGF did not alter either perfusate Ca2+ content or any of the metabolic parameters monitored. Additionally, experiments involving pulsatile infusion of either EGF or phenylephrine into livers demonstrated that, unlike the alpha 1-adrenergic receptor, homologous desensitization of the EGF receptor occurs. Such a homologous desensitization of the EGF receptor can explain the transient nature of EGF-elicited stimulation of various metabolic processes. Since protein kinase C activation by EGF can lead to receptor desensitization, experiments were performed with phorbol esters which either activate or do not alter protein kinase C activity. While the inactive phorbol ester 4 alpha-phorbol 12,13-didecanoate did not modulate the hepatic actions of EGF, activation of protein kinase C by 4 beta-phorbol 12-myristate 13-acetate (70 nM) abolished the ability of EGF to stimulate gluconeogenesis, tricarboxylic acid cycle activity and metabolic flux through the 2-oxoglutarate dehydrogenase complex.
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PMID:Regulation of hepatic energy metabolism by epidermal growth factor. 190 8

Vasopressin stimulated gluconeogenesis from proline in hepatocytes from starved rats; this was attributed to an activation of oxoglutarate dehydrogenase (EC 1.2.4.2) [Staddon & McGivan (1984) Biochem. J. 217, 477-483]. The role of Ca2+ in the activation mechanism was investigated. (1) In the absence of extracellular Ca2+, vasopressin caused a stimulation of gluconeogenesis and a decrease in cell oxoglutarate content that were markedly transient when compared with the effects in the presence of Ca2+. (2) Ca2+ added to cells stimulated for 2 min by vasopressin in the absence of extracellular Ca2+ sustained the initial effects of vasopressin. Ca2+ added 15 min after vasopressin, a time at which both the rate of gluconeogenesis and the cell oxoglutarate content were close to the control values, caused a stimulation of gluconeogenesis and a decrease in cell oxoglutarate content. (3) Under conditions of cell-Ca2+ depletion, vasopressin had no effect on gluconeogenesis or cell oxoglutarate content. (4) Ionophore A23187 stimulated gluconeogenesis and caused a decrease in cell oxoglutarate content, but the phorbol ester 4 beta-phorbol 12-myristate 13-acetate had no effects. (5) These data suggest that the initial activation of oxoglutarate dehydrogenase by vasopressin is dependent on an intracellular Ca2+ pool and independent of extracellular Ca2+. For activation of a greater duration, a requirement for extracellular Ca2+ occurs. The activation of oxoglutarate dehydrogenase by A23187 is consistent with a mechanism involving Ca2+, but the lack of effect of 4 beta-phorbol 12-myristate 13-acetate indicates that protein kinase C is not involved in the mechanism of activation by vasopressin.
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PMID:Ca2+-dependent activation of oxoglutarate dehydrogenase by vasopressin in isolated hepatocytes. 391 5