Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:4.6.1.1 (adenylate cyclase)
 19,190 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

It has been shown previously that the endogenous cannabinoid receptor ligand arachidonylethanolamide (anandamide 20:4, n-6) induces in vivo and in vivo effects typical of a cannabinoid partial agonist. We now report that the synthetic docosahexaenylethanolamide (anandamide 22:6, n-3) shows similar activities. In addition we show that these two anandamides, under certain experimental conditions, antagonize the effects of delta 9-THC both in vivo and in vitro. Thus a significant decrease in the potency of delta 9-THC-induced inhibition of adenylate cyclase was observed in N18TG2 neuroblastoma cells that were pretreated with low concentrations of anandamides. At these low concentrations of anandamides had no effect when applied alone. In vivo, Sabra or ICR mice were subjected to a tetrad of tests, designed to detect cannabinoid-induced effects. Mice pretreated (i.p.) with 10 mg/kg of delta 9-THC received injections with anandamides. Only low doses (0.0001-0.1 mg/kg) of the anandamides, which had no effects when administered alone, partially or fully inhibited the THC-induced effects. These findings suggest that the inhibition of delta 9-THC-induced effects by low doses of anandamides may be due to partial agonistic effects of these materials. It is possible that low doses of the anandamides are capable of activating a Gs protein mediated signaling pathway, or may cause an allosteric modulation of the cannabinoid receptor.
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PMID:Low doses of anandamides inhibit pharmacological effects of delta 9-tetrahydrocannabinol. 785 84

Cannabinoid receptors negatively regulate adenylate cyclase through a pertussis toxin-sensitive GTP-binding protein. In the present studies, signaling via the adenylate cyclase/cAMP pathway was investigated in the murine thymoma-derived T-cell line, EL4.IL-2. Northern analysis of EL4.IL-2 cells identified the presence of 4-kilobase CB2 but not CB1 receptor-subtype mRNA transcripts. Southern analysis of genomic DNA digests for the CB2 receptor demonstrated identical banding patterns for EL4.IL-2 cells and mouse-derived DNA, both of which were dissimilar to DNA isolated from rat. Treatment of EL4.IL-2 cells with either cannabinol or Delta9-THC disrupted the adenylate cyclase signaling cascade by inhibiting forskolin-stimulated cAMP accumulation which consequently led to a decrease in protein kinase A activity and the binding of transcription factors to a CRE consensus sequence. Likewise, an inhibition of phorbol 12-myristate 13-acetate (PMA)/ionomycin-induced interleukin 2 (IL-2) protein secretion, which correlated to decreased IL-2 gene transcription, was induced by both cannabinol and Delta9-THC. Further, cannabinoid treatment also decreased PMA/ionomycin-induced nuclear factor binding to the AP-1 proximal site of the IL-2 promoter. Conversely, forskolin enhanced PMA/ionomycin-induced AP-1 binding. These findings suggest that inhibition of signal transduction via the adenylate cyclase/cAMP pathway induces T-cell dysfunction which leads to a diminution in IL-2 gene transcription.
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PMID:Cannabinoid inhibition of adenylate cyclase-mediated signal transduction and interleukin 2 (IL-2) expression in the murine T-cell line, EL4.IL-2. 866 42

Delta9-Tetrahydrocannabinol (delta9-THC) binding to cannabinoid receptors induces an inhibition in adenylate cyclase activity through the engagement of a pertussis toxin-sensitive GTP-binding protein. In this study we investigated the ramifications of decreased cyclic AMP (cAMP) formation by delta9-THC on signaling events through the cAMP pathway distal to adenylate cyclase in mouse splenocytes. Delta9-THC treatment produced a marked and concentration-related decrease in forskolin-inducible protein kinase A (PKA) activity. This decrease in kinase activity was due to an inhibition in cAMP formation and not through a direct effect on the kinase as evidenced by the fact that PKA activity could not be modulated directly by delta9-THC in the presence of exogenous cAMP. One of the primary roles of PKA in this signaling pathway is to activate transcription factors for subsequent binding to cAMP response elements (CRE) present in the promoter region of cAMP-responsive genes. In the present studies, we observed that forskolin treatment of splenocytes resulted in a rapid activation of trans-acting factor binding to the CRE, which peaked at 30-60 min and whose binding was repressed concentration dependently in the presence of delta9-THC. As with forskolin, mitogenic stimulation including anti-CD3 mAb or phorbol ester plus ionomycin treatment of splenocytes induced CRE binding activity, which was maximal around 60 min and was suppressed by delta9-THC treatment. In conclusion, these data indicate that cAMP-mediated signal transduction is inhibited by delta9-THC and consequently leads to a decrease in the activation of transcription factors that bind to CRE regulatory sites.
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PMID:Inhibition of protein kinase A and cyclic AMP response element (CRE)-specific transcription factor binding by delta9-tetrahydrocannabinol (delta9-THC): a putative mechanism of cannabinoid-induced immune modulation. 926 Aug 75

Cannabinoids have a long history of consumption for recreational and medical reasons. The primary active constituent of the hemp plant Cannabis sativa is delta9-tetrahydrocannabinol (delta9-THC). In humans, psychoactive cannabinoids produce euphoria, enhancement of sensory perception, tachycardia, antinociception, difficulties in concentration and impairment of memory. The cognitive deficiencies seem to persist after withdrawal. The toxicity of marijuana has been underestimated for a long time, since recent findings revealed delta9-THC-induced cell death with shrinkage of neurons and DNA fragmentation in the hippocampus. The acute effects of cannabinoids as well as the development of tolerance are mediated by G protein-coupled cannabinoid receptors. The CB1 receptor and its splice variant CB1A, are found predominantly in the brain with highest densities in the hippocampus, cerebellum and striatum. The CB2 receptor is found predominantly in the spleen and in haemopoietic cells and has only 44% overall nucleotide sequence identity with the CB1 receptor. The existence of this receptor provided the molecular basis for the immunosuppressive actions of marijuana. The CB1 receptor mediates inhibition of adenylate cyclase, inhibition of N- and P/Q-type calcium channels, stimulation of potassium channels, and activation of mitogen-activated protein kinase. The CB2 receptor mediates inhibition of adenylate cyclase and activation of mitogen-activated protein kinase. The discovery of endogenous cannabinoid receptor ligands, anandamide (N-arachidonylethanolamine) and 2-arachidonylglycerol made the notion of a central cannabinoid neuromodulatory system plausible. Anandamide is released from neurons upon depolarization through a mechanism that requires calcium-dependent cleavage from a phospholipid precursor in neuronal membranes. The release of anandamide is followed by rapid uptake into the plasma and hydrolysis by fatty-acid amidohydrolase. The psychoactive cannabinoids increase the activity of dopaminergic neurons in the ventral tegmental area-mesolimbic pathway. Since these dopaminergic circuits are known to play a pivotal role in mediating the reinforcing (rewarding) effects of the most drugs of abuse, the enhanced dopaminergic drive elicited by the cannabinoids is thought to underlie the reinforcing and abuse properties of marijuana. Thus, cannabinoids share a final common neuronal action with other major drugs of abuse such as morphine, ethanol and nicotine in producing facilitation of the mesolimbic dopamine system.
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PMID:The effects of cannabinoids on the brain. 1036 32

Two subtypes of the mammalian cannabinoid receptor have been identified and successfully cloned since 1990. The CB(1) receptor is primarily located in the central nervous system and the CB(2) receptor is almost exclusively expressed in cells of the immune system. The CB(1) and CB(2) receptors are both G-protein coupled receptors and are involved in the inhibition of adenylate cyclase. The CB(2) receptor is of particular importance due to its involvement in signal transduction in the immune system, making it a potential target for therapeutic immune intervention. A number of these selective ligands are derivatives of traditional dibenzopyran based cannabinoids. These include the very recently synthesized (2'R)-1-methoxy-3-(2'-methylbutyl)- Delta (8)-THC (JWH-359) which has a 224 fold selectivity for the CB(2) receptor, readily comparable to the well known 1-deoxy-3-(1',1'-dimethylbutyl)- Delta (8)-THC (JWH-133) which has 200 fold selectivity for the CB(2) receptor. Several 9-hydroxyhexahydrocannabinols have also been synthesized and are found to be selective high affinity ligands for the CB(2) receptor. These are 1-deoxy-9beta-hydroxy-dimethylhexylhexahydrocannabinol (JWH-361, K(i) = 2.7 nM) and 1-deoxy-9beta-hydroxy-dimethylpentylhexahydrocannabinol (JWH-300, K(i) = 5.3 nM). CB(2) selective cannabi-mimetic indoles include 1-(2,3-dichlorobenzoyl)-2-methyl-3-(2-[1-morpholine]ethyl)-5-methoxyindole (L768242), (R)-3-(2-Iodo-5-nitrobenzoyl)-1-(1-methyl-2-piperidinylmethyl)-1H-indole (AM1241) and 1-propyl-2-methyl-3-(1-naphthoyl) indole (JWH-015), which exhibit significant selectivity for the CB(2) receptor coupled with weak affinity for the CB(1) receptor. Bristol-Meyer Squibb has produced a phenylalanine derived cannabimimetic indole which possesses high CB(2) affinity (K(i) = 8 nM) and very low affinity for the CB(1) receptor (K(i) = 4000 nM). This review will discuss the current advances and recent results in the structure-activity relationships (SAR) of selective ligands for the cannabinoid CB(2) receptor.
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PMID:Recent advances in the development of selective ligands for the cannabinoid CB(2) receptor. 1828 88

Previously, we found that in the lateral amygdala (LA) of the mouse, WIN55,212-2 decreases both glutamatergic and GABAergic synaptic transmission via activation of the cannabinoid receptor type 1 (CB1), yet produces an overall reduction of neuronal excitability. This suggests that the effects on excitatory transmission override those on inhibitory transmission. Here we show that CB1 activation by WIN55,212-2 and Delta(9)-THC inhibits long-term depression (LTD) of basal synaptic transmission in the LA, induced by low-frequency stimulation (LFS; 900 pulses/1 Hz). The CB1 agonist WIN55,212-2 blocked LTD via G(i/o) proteins, activation of inwardly rectifying K+ channels (K(ir)s), inhibition of the adenylate cyclase-protein kinase A (PKA) pathway, and PKA-dependent inhibition of voltage-gated N-type Ca2+ channels (N-type VGCCs). Interestingly, WIN55,212-2 effects on LTD were abolished in CB1 knock-out mice (CB1-KO), and in conditional mutants lacking CB1 expression only in GABAergic interneurons, but were still present in mutants lacking CB1 in principal forebrain neurons. LTD induction per se was unaffected by the CB1 antagonist SR141716A and was normally expressed in CB1-KO as well as in both conditional CB1 mutants. Our data demonstrate that activation of CB1 specifically located on GABAergic interneurons inhibits LTD in the LA. These findings suggest that CB1 expressed on either glutamatergic or GABAergic neurons play a differential role in the control of synaptic transmission and plasticity.
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PMID:Activation of CB1 specifically located on GABAergic interneurons inhibits LTD in the lateral amygdala. 1832 69


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