Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P51812 (mitogen-activated protein)
 10,636 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Following inducible expression in HEK293 cells, the human orexin-1 receptor was targeted to the cell surface but became internalized following exposure to the peptide agonist orexin A. By contrast, constitutive expression of the human cannabinoid CB1 receptor resulted in a predominantly punctate, intracellular distribution pattern consistent with spontaneous, agonist-independent internalization. Expression of the orexin-1 receptor in the presence of the CB1 receptor resulted in both receptors displaying the spontaneous internalization phenotype. Single cell fluorescence resonance energy transfer imaging indicated the two receptors were present as heterodimers/oligomers in intracellular vesicles. Addition of the CB1 receptor antagonist SR-141716A to cells expressing only the CB1 receptor resulted in re-localization of the receptor to the cell surface. Although SR-141716A has no significant affinity for the orexin-1 receptor, in cells co-expressing the CB1 receptor, the orexin-1 receptor was also re-localized to the cell surface by treatment with SR-141716A. Treatment of cells co-expressing the orexin-1 and CB1 receptors with the orexin-1 receptor antagonist SB-674042 also resulted in re-localization of both receptors to the cell surface. Treatment with SR-141716A resulted in decreased potency of orexin A to activate the mitogen-activated protein kinases ERK1/2 only in cells co-expressing the two receptors. Treatment with SB-674042 also reduced the potency of a CB1 receptor agonist to phosphorylate ERK1/2 only when the two receptors were co-expressed. These studies introduce an entirely novel pharmacological paradigm, whereby ligands modulate the function of receptors for which they have no significant inherent affinity by acting as regulators of receptor heterodimers.
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PMID:Orexin-1 receptor-cannabinoid CB1 receptor heterodimerization results in both ligand-dependent and -independent coordinated alterations of receptor localization and function. 1701 51

The receptor(s) used by cannabinoids to relax vascular smooth muscle is unknown. Here, we investigated the effects of 2-arachidonylglyceryl ether (2-AG ether), a metabolically stable endocannabinoid, and abnormal cannabidiol (abn-CBD) on relaxation of permeabilized pulmonary arterial strips monitored with force, and on extracellular signal-regulated mitogen-activated protein kinases (ERK1/2) phosphorylation in permeabilized vascular smooth muscle cells using immunoblotting. We found that 2-AG ether and abn-CBD caused relaxation and increased phosphorylation of ERK1/2. 2-AG ether effects were completely abolished by N-(piperidin-1-yl)-5-(4-iodophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamide (AM251), and N-(piperidin-1-yl)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamide (SR141716A), and partially blocked by (-)-1.3-dimethoxy-2-(3-3,4-trans-p-menthadien-(1,8)-yl)-orcinol (O-1918). In contrast, abn-CBD effects were completely abolished by O-1918, and only partially blocked by AM251, and SR141716A. Both 2-AG ether and abn-CBD effects were partially blocked by pertussis toxin, an inhibitor of Gi/o proteins. PD98059, an inhibitor of mitogen activated protein kinase kinase (MEK), completely abolished the relaxation, but only partially blocked the increased phosphorylation of ERK1/2 by 2-AG ether. In contrast, abn-CBD-induced relaxation was partially blocked and the increased phosphorylation of ERK1/2 was abolished by PD98059. These findings suggest that 2-AG ether and abn-CBD-induced vascular smooth muscle relaxation are mediated by the cannabinoid CB1 receptor, and the abn-CBD receptor, respectively, and are modulated by cross-talk between the receptors. These responses occur mainly by coupling to pertussis toxin sensitive G proteins, but also, in part independent of these G proteins, which have been classically thought to initiate MEK/ERK1/2 signaling to relax vascular smooth muscle.
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PMID:2-Arachidonylglyceryl ether and abnormal cannabidiol-induced vascular smooth muscle relaxation in rabbit pulmonary arteries via receptor-pertussis toxin sensitive G proteins-ERK1/2 signaling. 1729 52

Solar UV irradiation is an important carcinogen that leads to the development of skin cancer, which is the most common human cancer. However, the receptors that mediate UV-induced skin carcinogenesis have not yet been unequivocally identified. Here we showed that UV irradiation directly activates cannabinoid receptors 1 and 2 (CB1/2). Notably, our data indicated that the absence of the CB1/2 receptors in mice results in a dramatic resistance to UVB-induced inflammation and a marked decrease in UVB-induced skin carcinogenesis. A marked attenuation of UVB-induced activation of mitogen-activated protein kinases and nuclear factor- kappaB was associated with CB1/2 deficiency. These data provide direct evidence indicating that the CB1/2 receptors play a key role in UV-induced inflammation and skin cancer development.
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PMID:The cannabinoid receptors are required for ultraviolet-induced inflammation and skin cancer development. 1848 86

This study was conducted to test the effects of 2-arachidonylglycerol (2-AG), an endocannabinoid, on aqueous humor outflow facility, to study the cellular mechanisms of 2-AG, and to investigate the possible existence and activity of monoacylgylcerol lipase (MGL), a 2-AG metabolic enzyme, in the trabecular meshwork (TM). The effects of 2-AG on aqueous humor outflow facility were measured using an anterior segment perfused organ culture model. The expression and activity of MGL in TM tissues were assessed using Western blot analysis and an enzyme activity assay respectively. 2-AG induced activation of p42/44 mitogen-activated protein (MAP) kinase was determined by Western blot analysis using an anti-phospho p42/44 MAP kinase antibody. AlexaFluor 488-labeled phalloidin staining was used to examine actin filament in cultured TM cells. Administration of 10nM of 2-AG caused a transient enhancement of aqueous humor outflow. In the presence of 100nM of LY2183240, an inhibitor of MGL, the effect of 10nM of 2-AG on outflow was prolonged by at least 4h. The 2-AG-induced enhancement of outflow was blocked by SR141716A, a CB1 antagonist, and SR144528, a CB2 antagonist. In Western blot studies, a 35kDa band representing MGL was detected on TM tissues with an anti-MGL antibody. The 2-AG enzymatic hydrolysis activity was detected in TM tissues and this activity was reduced by 70.1+/-5.3% with the addition of 100 nM of LY2183240. Treatment of trabecular meshwork cells with 10nM of 2-AG plus 100 nM LY2183240 for 5h evoked phosphorylation of p42/44 MAP kinase. The 2-AG-induced enhancement of p42/44 MAP kinase phosphorylation was blocked by pretreatment with SR141716A, SR144528, as well as PD98059, an inhibitor of the p42/44 MAP kinase pathway. In addition, the outflow-enhancing effect of 2-AG was blocked by pretreatment with PD98059. Furthermore, treatment with 2-AG plus LY2183240 caused rounding of TM cells and a reduction of actin stress fibers in TM cells. Pretreatment with SR141716A, SR144528, and PD98059 blocked these 2-AG-induced morphology and cytoskeleton changes in TM cells. In conclusion, the results from this study demonstrate that administration of 2-AG increases aqueous humor outflow facility and this effect of 2-AG is mediated through both the CB1 and CB2 cannabinoid receptors. In addition, this study reveals the existence and the activity of MGL, a 2-AG metabolizing enzyme, in the TM tissues. Furthermore, this study suggests that 2-AG-induced enhancement of outflow facility involves the p42/44 MAP kinase signaling pathway and changes in actin cytoskeletons in TM cells.
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PMID:Aqueous humor outflow effects of 2-arachidonylglycerol. 1859 52

CB1 receptors are G-protein coupled receptors (GPCRs) abundant in neurons, in which they modulate neurotransmission. The CB(1) receptor influence on memory and learning is well recognized, and disease states associated with CB(1) receptors are observed in addiction disorders, motor dysfunction, schizophrenia, and in bipolar, depression, and anxiety disorders. Beyond the brain, CB(1) receptors also function in liver and adipose tissues, vascular as well as cardiac tissue, reproductive tissues and bone. Signal transduction by CB(1) receptors occurs through interaction with Gi/o proteins to inhibit adenylyl cyclase, activate mitogen-activated protein kinases (MAPK), inhibit voltage-gated Ca(2+) channels, activate K(+) currents (K(ir)), and influence Nitric Oxide (NO) signaling. CB(1) receptors are observed in internal organelles as well as plasma membrane. beta-Arrestins, adaptor protein AP-3, and G-protein receptor-associated sorting protein 1 (GASP1) modulate cellular trafficking. Cannabinoid Receptor Interacting Protein1a (CRIP1a) is an accessory protein whose function has not been delineated. Factor Associated with Neutral sphingomyelinase (FAN) regulates ceramide signaling. Such diversity in cellular signaling and modulation by interacting proteins suggests that agonists and allosteric modulators could be developed to specifically regulate unique, cell type-specific responses.
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PMID:CB(1) cannabinoid receptors and their associated proteins. 2016 26

Cannabinoids have been shown to exert analgesic and anti-inflammatory effects, and the effects of cannabinoids are mediated primarily by cannabinoid receptors 1 and 2 (CB1and CB2). Both CB1 and CB2 are present in bladders of various species, including human, monkey, and rodents, and it appears that CB2 is highly expressed in urothelial cells. We investigated whether treatment with the CB2 agonist GP1a alters severity of experimental cystitis induced by acrolein and referred mechanical hyperalgesia associated with cystitis. We also investigated whether the mitogen-activated protein kinases (MAPK), ERK1/2, p38, and JNK are involved in the functions of CB2. We found that treatment with the selective CB2 agonist GP1a (1-10 mg/kg, ip) inhibited the severity of bladder inflammation 3 h after intravesical instillation of acrolein in a dose-dependent manner, and inhibition reached significance at a dose of 10 mg/kg (P < 0.05). Treatment with GP1a (10 mg/kg) inhibited referred mechanical hyperalgesia associated with cystitis (P < 0.05). The inhibitory effects of the CB2 agonist were prevented by the selective CB2 antagonist AM630 (10 mg/kg, sc). We further demonstrated the inhibitory effects of CB2 appear to be at least partly mediated by reducing bladder inflammation-induced activation of ERK1/2 MAPK pathway. The results of the current study indicate that CB2 is a potential therapeutic target for treatment of bladder inflammation and pain in patients.
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PMID:Activation of cannabinoid receptor 2 inhibits experimental cystitis. 2351 18

Similar to clinically used antidepressants, cannabinoids can also regulate anxiety and depressive symptoms. Although the mechanisms of these effects are not completely understood, recent evidence suggests that changes in endocannabinoid system could be involved in some actions of antidepressants. Chronic antidepressant treatment modifies the expression of CB1 receptors and endocannabinoid (EC) content in brain regions related to mood and anxiety control. Moreover, both antidepressant and cannabinoids activate mitogen-activated protein (MAP) kinase and phosphoinositide 3-kinase(PI3-K)/Akt or PKB signaling, intracellular pathways that regulate cell proliferation and neural cell survival. Facilitation of hippocampal neurogenesis is proposed as a common effect of chronic antidepressant treatment. Genetic or pharmacological manipulations of cannabinoid receptors (CB1 and CB2) or enzymes responsible for endocannabinoid-metabolism have also been shown to control proliferation and neurogenesis in the hippocampus. In the present paper we reviewed the studies that have investigated the potential contribution of cannabinoids and neurogenesisto antidepressant effects. Considering the widespread brain distribution of the EC system, a better understanding of this possible interaction could contribute to the development of therapeutic alternatives to mood and anxiety disorders.
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PMID:Cannabinoids, Neurogenesis and Antidepressant Drugs: Is there a Link? 2417 63


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