Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.7.11.11 (AMPK)
 12,425 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The effects of submaximal doses of AlF4- to mobilize hepatocyte Ca2+ were potentiated by glucagon (0.1-1 nM) and 8-p-chlorophenylthio-cAMP. A similar potentiation by glucagon of submaximal doses of vasopressin, angiotensin II, and alpha 1-adrenergic agonists has been previously shown (Morgan, N. G., Charest, R., Blackmore, P. F., and Exton, J. H. (1984) Proc. Natl. Acad. Sci. U. S. A. 81, 4208-4212). When hepatocytes were pretreated with the protein kinase C activator 4 beta-phorbol 12 beta-myristate 13 alpha-acetate (PMA), the effects of AlF4- to mobilize Ca2+, increase myo-inositol 1,4,5-trisphosphate (IP3), and activate phosphorylase were attenuated. Treatment of hepatocytes with PMA likewise inhibits the ability of vasopressin, angiotensin II, and alpha 1-adrenergic agonists to increase IP3 and mobilize Ca2+ (Lynch, C. J., Charest, R., Bocckino, S. B., Exton, J. H., and Blackmore, P. F. (1985) J. Biol. Chem. 260, 2844-2851). In contrast, the ability of AlF4- or angiotensin II to lower cAMP or inhibit glucagon-mediated increases in cAMP was unaffected by PMA. The ability of AlF4- to lower cAMP was attenuated in hepatocytes from animals treated with islet-activating protein, whereas Ca2+ mobilization was not modified. These results suggest that the lowering of cAMP induced by AlF4- and angiotensin II was mediated by the inhibitory guanine nucleotide-binding regulatory protein of adenylate cyclase, whereas Ca2+ mobilization was not. Addition of glucagon, forskolin, or 8CPT-cAMP to hepatocytes raised IP3 and mobilized Ca2+. Both effects were blocked by PMA pretreatment, whereas cAMP and phosphorylase a levels were only minimally affected by PMA. The mobilization of Ca2+ induced by cAMP in hepatocytes incubated in low Ca2+ media was not additive with that induced by maximally effective doses of vasopressin, angiotensin II, or alpha 1-adrenergic agonists, indicating that the Ca2+ pool(s) affected by agents which increase cAMP is the same as that affected by Ca2+-mobilizing hormones which do not increase cAMP. These findings support the proposal that AlF4- mimics the effects of the Ca2+-mobilizing hormones in hepatocytes by activating a guanine nucleotide-binding regulatory protein (Np) which couples the hormone receptors to a phosphatidylinositol 4,5-bisphosphate (PIP2)-specific phosphodiesterase. They also suggest that Np, PIP2 phosphodiesterase, or a factor involved in their interaction is activated following phosphorylation by cAMP-dependent protein kinase and inhibited after phosphorylation by protein kinase C.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Studies on the hepatic calcium-mobilizing activity of aluminum fluoride and glucagon. Modulation by cAMP and phorbol myristate acetate. 242 66

The effects of agonists at mu and delta opioid receptors were compared by measuring membrane currents under voltage clamp from neurons of the rat nucleus locus coeruleus and guinea pig submucous plexus. In each tissue, the appropriate selective agonist (Tyr-D-Ala-Gly-MePhe-Gly-ol for mu receptors in locus coeruleus or Tyr-D-Pen-Gly-Phe-D-Pen for delta receptors in submucous plexus) increased the conductance of an inwardly rectifying potassium conductance and strongly hyperpolarized the membrane. The properties of the potassium conductance affected by the two opioids could not be distinguished. Experiments with intracellular application of guanosine 5'-[gamma-thio]triphosphate indicated that a guanine nucleotide-binding regulatory protein was involved in the coupling between opioid receptor and potassium channel, but there was no evidence for activation of either cAMP-dependent protein kinase or protein kinase C. It is noted that a number of vertebrate neurotransmitter receptors are coupled to potassium channels. The potassium conductance associated with these channels has properties similar to the conductance activated by mu and delta opioids; this family includes the following receptors: acetylcholine M2, norepinephrine alpha 2, dopamine D2, 5-hydroxytryptamine 5-HT1, adenosine A1, gamma-aminobutyric acid GABAB, and somatostatin. It is suggested that this conductance is a conserved neuronal effector coupled to one of the receptor types that mediates the effects of each of several major transmitters. The mu and delta opioid receptors appear to be unusual in that both utilize this same effector mechanism.
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PMID:Mu and delta receptors belong to a family of receptors that are coupled to potassium channels. 244 52

We report here that, contrary to previously reported findings, treatment of S49 wild-type (WT) lymphoma cells with 0-50 nM epinephrine resulted in a heterologous desensitization of adenylyl cyclase (EC 4.6.1.1)--that is, epinephrine and prostaglandin E1 (PGE1) stimulations of adenylyl cyclase were reduced. Observation of this heterologous desensitization required the assay of adenylyl cyclase with submillimolar concentrations of Mg2+ and low concentrations of epinephrine. Also, whereas previously there had been no evidence for any role of cAMP-dependent protein kinase in the desensitization of the WT beta-adrenergic receptor, our data comparing the characteristics of the desensitization in WT, kin-, and cyc- lymphoma cells [where kin- and cyc- refer to variants of S49 WT cells lacking cAMP-dependent protein kinase activity (kin-) and the alpha subunit of the stimulatory guanine nucleotide-binding regulatory protein (cyc-)] now suggest that cAMP-dependent protein kinase mediates the heterologous desensitization of adenylyl cyclase. Specifically, we found that only the WT cells exhibited epinephrine-induced heterologous desensitization. The kin- and cyc- cells exhibited only homologous desensitization, and much higher concentrations of epinephrine were required to elicit the homologous desensitization in the variants relative to the heterologous desensitization of the WT. Treatment of WT and cyc- cells with dibutyryl cAMP or treatment of WT with forskolin or PGE1 caused the heterologous desensitization of adenylyl cyclase, indicating that neither receptor occupancy nor activation of adenylyl cyclase was necessary for the heterologous desensitization.
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PMID:Activation of cAMP-dependent protein kinase is required for heterologous desensitization of adenylyl cyclase in S49 wild-type lymphoma cells. 283 Jun 19

Muscarinic agonists inhibit cyclic AMP (cAMP)-induced phosphorylation of the cardiac protein phospholamban. The mechanism of this muscarinic inhibition of phosphorylation of phospholamban appears to occur at more than one level in the series of reactions comprising the adenylate cyclase, cAMP-dependent protein kinase system. Muscarinic agonists attenuate hormone and drug stimulation of cardiac adenylate cyclase. This results in reduced tissue levels of cAMP and diminished phosphorylation of cardiac proteins and consequent inhibition of biochemical and inotropic effects of drugs that act via cAMP. The mechanism of muscarinic inhibition of adenylate cyclase is only partially understood, but probably involves the inhibitory guanine nucleotide-binding regulatory protein. In addition to the inhibition of adenylate cyclase, muscarinic agonists appear to be able to inhibit the effects of cAMP. The mechanism for this second effect of muscarinic agonists is unknown.
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PMID:Mechanisms of muscarinic modulation of protein phosphorylation in intact ventricles. 608 11

Behavioral studies have shown that mechanical hyperalgesia induced by intradermal injection of prostaglandin E2 is blocked by inhibitors of the cAMP second messenger system. Similarly, injection of prostaglandin E2 also induces a decrease in mechanical threshold and an increase in the number of action potentials elicited by test stimuli in most C-fibre nociceptors. This change is called sensitization. To further evaluate the degree of correlation between primary afferent sensitization and mechanical hyperalgesia, we conducted a study to evaluate the effect of agents known to block the cAMP second messenger system and behavioral manifestations of mechanical hyperalgesia following injection of prostaglandin E2. The agents tested were guanosine 5'-O-(2-thiodiphosphate), an inhibitor of stimulatory guanine nucleotide-binding regulatory proteins; 2',5'-dideoxyadenosine, an inhibitor of adenylyl cyclase; and Walsh Inhibitor Peptide, an inhibitor of cAMP-dependent protein kinase. Single fibre electrophysiologic studies of 138 C-fibres, innervating the dorsum of the hind paw, was done in male Sprague-Dawley rats. The number of spikes evoked by a 10 s application of a threshold von Frey hair were determined before and after intradermal injection of test agents administered alone and in combination with prostaglandin E2. Injection of prostaglandin E2 with the test agent vehicle (saline or distilled water) resulted in a significant decrease in von Frey hair threshold and an increase in the number of spikes generated in response to threshold von Frey hairs. In contrast, co-injection of prostaglandin E2 with guanosine-5'-O-(2-thiodiphosphate), 2',5'-dideoxyadenosine or Walsh inhibitor peptide did not result in a significant decrease in von Frey hair mechanical threshold or increase in the number of spikes generated to the threshold stimuli, compared with vehicle/prostaglandin E2. It is suggested that guanosine 5'-O-(2-thiodiphosphate), 2',5'-dideoxyadenosine and Walsh inhibitor protein inhibited prostaglandin E2 sensitization of primary afferent C-fibres by inhibiting a stimulatory guanine nucleotide-binding regulatory protein, adenylyl cyclase, and protein kinase A, respectively. These results support the hypothesis that primary afferent sensitization by prostaglandin E2 underlies prostaglandin E2-induced hyperalgesia.
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PMID:Sensitization of C-fibres by prostaglandin E2 in the rat is inhibited by guanosine 5'-O-(2-thiodiphosphate), 2',5'-dideoxyadenosine and Walsh inhibitor peptide. 883 7