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 primary structure of phenylalanine hydroxylase purified from rat liver was investigated with high speed gel filtration chromatography, cyanogen bromide cleavage and end group analyses of polypeptides derived from the enzyme. On gel filtration in the presence of 6M guanidine hydrochloride, the enzyme gave a single peak corresponding to a molecular weight of 52,000. In the same system the enzyme that had been cleaved with cyanogen bromide gave two peptides (CB1, Mr = 32,800 and CB2, Mr = 20,400). Sequence studies showed that the alignment of these two peptides was CB1 - CB2. Furthermore, in experiments using 32P phosphorylated enzyme, the site of phosphorylation by cAMP-dependent protein kinase was found to be located on the CB1 peptide. The NH2-terminus of this enzyme, which was found to be blocked, was shown to be N-acetylalanine. By both carboxypeptidase A digestion and hydrazinolysis, the carboxyl terminus was identified as serine. These data indicate that the phenylalanine hydroxylase molecule from rat liver is composed of subunits which are homogenous or, at least, very similar in their primary structure.
 ...
PMID:Studies on the primary structure of rat liver phenylalanine hydroxylase. 397 94

The present work was undertaken to study the metabolic response of C6 glioma cells to physiologically relevant doses of delta9-tetrahydrocannabinol (THC), the major active component of marijuana. At those concentrations (i.e. nanomolar range), THC produced a dose-dependent increase in the rates of glucose oxidation to CO2 and glucose incorporation into phospholipids and glycogen. The THC-induced stimulation of glucose utilization was (i) dose-dependent up to 100 nM THC, (ii) mimicked by the synthetic cannabinoid HU-210, and (iii) prevented by pertussis toxin and the CB1 receptor antagonist SR141716A. In contrast to THC, forskolin markedly depressed CO2 production, phospholipid synthesis and glycogen synthesis from glucose. The forskolin-induced inhibition of glucose utilization was (i) mimicked by dibutyryl-cAMP, and (ii) prevented by THC, HU-210 and H-7, an inhibitor of the cAMP-dependent protein kinase. Likewise, THC was able to antagonize in part the forskolin-induced elevation of intracellular cAMP concentration, and this antagonistic effect was prevented by SR141716A. However, THC per se did not affect basal cAMP concentration. Results thus indicate that physiologically relevant doses of THC stimulate glucose metabolism in C6 glioma cells through a cannabinoid receptor-mediated process. Although cannabinoid receptors may be coupled to inhibition of adenylyl cyclase in C6 glioma cells, this does not seem to be the mechanism involved in the THC-induced stimulation of glucose metabolism.
 ...
PMID:Delta9-tetrahydrocannabinol stimulates glucose utilization in C6 glioma cells. 936 16

In hippocampus endocannabinoids modulate synaptic function and plasticity and increase tyrosine phosphorylation of several proteins, including focal adhesion kinase (FAK). Autophosphorylation of FAK on Tyr-397 is generally a critical step for its activation, allowing the recruitment of Src family kinases, and phosphorylation of FAK and associated proteins. We have examined the mechanisms of the regulation of FAK by cannabinoids in rat and mouse hippocampal slices. Anandamide and 2-arachidonoylglycerol, two endocannabinoids, and Delta9-tetrahydrocannabinol, stimulated tyrosine phosphorylation of FAK+6,7, a neuronal splice isoform of FAK, on several residues including Tyr-397. Cannabinoids increased phosphorylation of p130-Cas, a protein associated with FAK, but had no effect on PYK2, a tyrosine kinase related to FAK and enriched in hippocampus. Pharmacological experiments and the use of knockout mice demonstrated that the effects of cannabinoids were mediated through CB1 receptors. These effects were sensitive to manipulation of cAMP-dependent protein kinase, suggesting that they were mediated by inhibition of a cAMP pathway. PP2, an Src family kinase inhibitor, prevented the effects of cannabinoids on p130-Cas and on FAK+6,7 tyrosines 577 and 925, but not 397, indicating that FAK autophosphorylation was upstream of Src family kinases in response to CB1-R stimulation. Endocannabinoids increased the association of Fyn, but not Src, with FAK+6,7. In hippocampal slices from Fyn -/- mice, the levels of p130-Cas were increased, and the effects of endocannabinoids on tyrosine phosphorylation, including of Tyr-397, were completely abolished. These results demonstrate the specific functional association of Fyn with FAK+6,7 in a pathway regulated by endocannabinoids, in which Fyn may play roles dependent and independent of its catalytic activity.
 ...
PMID:Dual role of Fyn in the regulation of FAK+6,7 by cannabinoids in hippocampus. 1146 87

The present study demonstrates a novel stimulatory effect of a cannabinoid agonist on calcium channels. DALN (1 nM) potentiated 45Ca(2+)-uptake by N18TG2 neuroblastoma cells, an effect that was abolished by the specific CB1 receptor antagonist SR141716A. The stimulation of 45Ca(2+)-uptake by DALN was resistant to pertussis toxin (PTX), suggesting that Gi/Go GTP-binding proteins did not mediate this effect. Furthermore, PTX unmasked a stimulatory effect of a high concentration of DALN (1 microM), which by itself failed to stimulate calcium uptake in naive cells. The stimulatory effect of DALN on calcium entry to the cells was blocked by nicardipine but not by omega-conotoxin GVIA, indicating the entry of calcium through L-type voltage-dependent calcium channels. Blocking cAMP-dependent protein kinase (PKA) by H-89 completely eliminated the elevation in calcium uptake, while blocking protein kinase C (PKC) by chelerythrine and calphostine-C only partially attenuated the stimulation. Blocking calmodulin by W-7 revealed a similar partial inhibition of the stimulatory effect of DALN. Hence, we suggest a cannabinoid-specific, PTX-insensitive, stimulatory effect on L-type voltage-dependent calcium channels, which is mediated by PKA and modulated by PKC and calmodulin.
 ...
PMID:The cannabinoid agonist DALN positively modulates L-type voltage-dependent calcium-channels in N18TG2 neuroblastoma cells. 1200 36

The mesolimbic dopamine system and cAMP-dependent/protein kinase A (PKA) pathways are strongly implicated in addictive behaviors. Here we determine the role of dopamine D2 receptors (D2) in PKA signaling responses to delta-opioid (DOR) and cannabinoid (CB1) receptors. We find in NG108-15/D2 cells and in cultured primary neurons that a brief exposure to saturating concentrations of DOR and CB1 agonists increases cAMP, promotes PKA C alpha translocation and increases cAMP-dependent gene expression. Activation of PKA signaling is mediated by Gi-beta gamma dimers. Importantly, subthreshold concentrations of DOR or CB1 agonists with D2 agonists, which are without effect when added separately, together activate cAMP/PKA signaling synergistically. There is also synergy between DOR or CB1 with ethanol, another addicting agent. In all instances, synergy requires adenosine activation of adenosine A2 receptors and is mediated by beta gamma dimers. Synergy by this molecular mechanism appears to confer hypersensitivity to opioids and cannabinoids while simultaneously increasing the sensitivity of D2 signaling when receptors are expressed on the same cells. This mechanism may account, in part, for drug-induced activation of medium spiny neurons in the nucleus accumbens.
 ...
PMID:Addicting drugs utilize a synergistic molecular mechanism in common requiring adenosine and Gi-beta gamma dimers. 1460 13

Exogenously administered cannabinoids are neuroprotective in several different cellular and animal models. In the current study, two cannabinoid CB1 receptor ligands (WIN 55,212-2, CP 55,940) markedly reduced hippocampal cell death, in a time-dependent manner, in cultured neurons subjected to high levels of NMDA (15 microM). WIN 55,212-2 was also shown to inhibit the NMDA-induced increase in intracellular calcium concentration ([Ca2+](i)) indicated by FURA-2 fluorescence imaging in the same cultured neurons. Changes in [Ca2+](i) occurred with similar concentrations (25-100 nM) and in the same time-dependent manner (pre-exposure 1-15 min) as CB1 receptor mediated neuroprotective actions. Both effects were blocked by the CB1 receptor antagonist SR141716A. An underlying mechanism was indicated by the fact that (1) the NMDA-induced increase in [Ca2+](i) was inhibited by ryanodine, implicating a ryanodine receptor (RyR) coupled intracellular calcium channel, and (2) the cannabinoid influence involved a reduction in cAMP cAMP-dependent protein kinase (PKA) dependent phosphorylation of the same RyR levels that regulate channel. Moreover the time course of CB1 receptor mediated inhibition of PKA phosphorylation was directly related to effective pre-exposure intervals for cannabinoid neuroprotection. Control studies ruled out the involvement of inositol-trisphosphate (IP3) pathways, enhanced calcium reuptake and voltage sensitive calcium channels in the neuroprotective process. The results suggest that cannabinoids prevent cell death by initiating a time and dose dependent inhibition of adenylyl cyclase, that outlasts direct action at the CB1 receptor and is capable of reducing [Ca2+](i) via a cAMP/PKA-dependent process during the neurotoxic event.
 ...
PMID:Cannabinoids produce neuroprotection by reducing intracellular calcium release from ryanodine-sensitive stores. 1591 Aug 85

CB1 receptor agonists increase the state of phosphorylation of the dopamine and cAMP-regulated phosphoprotein of 32 kDa (DARPP-32) at the cAMP-dependent protein kinase site, Thr 34. This effect, which occurs in the medium spiny neurons of the striatum, has been proposed to mediate the motor depressant action of cannabinoids. In this study, we have examined the effect produced by systemic administration of Delta(9)-tetrahydrocannabinol (THC), the major component of marihuana and hashish, on DARPP-32. We show that THC increases DARPP-32 phosphorylation at Thr 34 both in dorsal striatum and nucleus accumbens. Time-course and dose-response experiments indicate that DARPP-32 phosphorylation is maximal 30 min following administration of 10mg/kg of THC. The THC-mediated increase in DARPP-32 phosphorylation is reduced by administration of the CB1 receptor antagonist, SR141716A (3mg/kg). A similar attenuation of the effect of THC is also exerted by suppression of cAMP signaling achieved using the dopamine D1 receptor antagonist, SCH23390 (0.125 mg/kg), or the adenosine A2A receptor antagonist, KW6002 (3mg/kg). These results indicate that, in the striatum, THC promotes PKA-dependent phosphorylation of DARPP-32 in striatal medium spiny neurons expressing dopamine D1 and adenosine A2A receptors.
 ...
PMID:Regulation of DARPP-32 phosphorylation by Delta9-tetrahydrocannabinol. 1768 97

Endocannabinoids are well established as inhibitors of chemical synaptic transmission via presynaptic activation of the cannabinoid type 1 receptor (CB1R). Contrasting this notion, we show that dendritic release of endocannabinoids mediates potentiation of synaptic transmission at mixed (electrical and chemical) synaptic contacts on the goldfish Mauthner cell. Remarkably, the observed enhancement was not restricted to the glutamatergic component of the synaptic response but also included a parallel increase in electrical transmission. This effect involved the activation of CB1 receptors and was indirectly mediated via the release of dopamine from nearby varicosities, which in turn led to potentiation of the synaptic response via a cAMP-dependent protein kinase-mediated postsynaptic mechanism. Thus, endocannabinoid release can potentiate synaptic transmission, and its functional roles include the regulation of gap junction-mediated electrical synapses. Similar interactions between endocannabinoid and dopaminergic systems may be widespread and potentially relevant for the motor and rewarding effects of cannabis derivatives.
 ...
PMID:Potentiation of electrical and chemical synaptic transmission mediated by endocannabinoids. 1809 17

The anti-tumoral effects of cannabinoids have been described in different tumor systems, including pancreatic adenocarcinoma, but their mechanism of action remains unclear. We used cannabinoids specific for the CB1 (ACPA) and CB2 (GW) receptors and metabolomic analyses to unravel the potential pathways mediating cannabinoid-dependent inhibition of pancreatic cancer cell growth. Panc1 cells treated with cannabinoids show elevated AMPK activation induced by a ROS-dependent increase of AMP/ATP ratio. ROS promote nuclear translocation of GAPDH, which is further amplified by AMPK, thereby attenuating glycolysis. Furthermore, ROS determine the accumulation of NADH, suggestive of a blockage in the respiratory chain, which in turn inhibits the Krebs cycle. Concomitantly, inhibition of Akt/c-Myc pathway leads to decreased activity of both the pyruvate kinase isoform M2 (PKM2), further downregulating glycolysis, and glutamine uptake. Altogether, these alterations of pancreatic cancer cell metabolism mediated by cannabinoids result in a strong induction of autophagy and in the inhibition of cell growth.
 ...
PMID:Cannabinoids inhibit energetic metabolism and induce AMPK-dependent autophagy in pancreatic cancer cells. 2376 45

The nutritional compound capsaicin inhibits the invasion of many types of human cancers. The clinical development of capsaicin as an anti-cancer drug is limited due to its unfavorable side effects like burning sensation, stomach cramps, gut pain and nausea. This study compared the anti-invasive activity of capsaicin to non-pungent long chain capsaicin analogs, namely arvanil and olvanil, in human small cell lung cancer cells. Boyden chamber invasion assays revealed that arvanil and olvanil displayed improved anti-invasive activity relative to capsaicin in human SCLC cells. The results of the Boyden chamber assay were confirmed by the spherical invasion assay, and similar results were obtained. The anti-invasive activity of arvanil, olvanil and capsaicin were independent of TRPV and CB1 receptors. Furthermore, the anti-invasive activity of arvanil, olvanil and capsaicin was mediated by the AMPK pathway. Depletion of AMPK levels by siRNA methodology abrogated the anti-invasive activity of arvanil, olvanil and capsaicin. The non-pungent capsaicin analogs arvanil and olvanil display improved anti-invasive activity relative to capsaicin in human SCLC cells. These agents may represent the second generation of capsaicin-like compounds which are more potent than the parent molecule and have a better side effect profile.
 ...
PMID:Non-pungent long chain capsaicin-analogs arvanil and olvanil display better anti-invasive activity than capsaicin in human small cell lung cancers. 2719 29


1 2 Next >>