Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0043167 (pertussis)
 19,595 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

LY320135 is a selective antagonist for the brain CB1 receptor, having greater than 70-fold higher affinity for the CB1 than the peripheral CB2 receptor. The Ki values for LY320135 at the CB1 and CB2 receptors, transfected and stably expressed in cell lines, were 224 nM and > 10 microM, respectively. Similar Ki values were measured in binding studies performed on cerebellum and spleen membrane preparations endogenously expressing the CB1 (203 nM) and CB2 (> 10 microM) receptors, respectively. LY320135 functionally reversed anandamide-mediated adenylate cyclase inhibition in Chinese hamster ovary (CHO) cells stably expressing the CB1 receptor. Pertussis toxin treatment of CHO cells expressing the CB1 receptor attenuated the anandamide-mediated inhibition of adenylate cyclase and unmasked a stimulatory effect of anandamide on adenylate cyclase. The stimulatory component was blocked with LY320135. This compound also blocked WIN 55212-2-mediated inhibition of N-type calcium channels and activation of inwardly rectifying potassium channels in N18 and AtT-20-CB2 cells, respectively. LY320135 is a promising lead compound for the further development of novel, potent and selective cannabinoid antagonists of novel structure.
 ...
PMID:LY320135, a novel cannabinoid CB1 receptor antagonist, unmasks coupling of the CB1 receptor to stimulation of cAMP accumulation. 943 90

The effects of anandamide and the cannabinoid receptor agonists WIN 55212-2 and CP 55940 on the evoked formation of cyclic AMP were compared in cultured neurons and astrocytes from the cerebral cortex and striatum of mouse embryos. The three compounds inhibited the isoproterenol-induced accumulation of cyclic AMP in neuronal cells, and these responses were blocked by the selective CB1 receptor antagonist SR 141716A. The three agonists were more potent in cortical than striatal neurons. Interestingly, WIN 55212-2, CP 55940 and anandamide also inhibited the isoproterenol-evoked accumulation of cyclic AMP in astrocytes but, in contrast to WIN 55212-2 and CP 55940, anandamide was much more potent in striatal than cortical astrocytes. Inhibition was prevented by pertussis toxin pretreatment, but not blocked by SR 141716A. Therefore, G-protein-coupled receptors, distinct from CB1 receptors, are involved in these astrocytic responses. Moreover, specific binding sites for [3H]-SR 141716A were found in neurons but not astrocytes. Furthermore, using a polyclonal CB1 receptor antibody, staining was observed in striatal and cortical neurons, but not in striatal and cortical astrocytes. Taken together, these results suggest that glial cells possess G-protein-coupled receptors activated by cannabinoids distinct from the neuronal CB1 receptor, and that glial cells responses must be taken into account when assessing central effects of cannabinoids.
 ...
PMID:Anandamide and WIN 55212-2 inhibit cyclic AMP formation through G-protein-coupled receptors distinct from CB1 cannabinoid receptors in cultured astrocytes. 1005 70

Intracerebroventricular (i.c.v.) administration to mice of delta9-tetrahydrocannabinol (delta9-THC), WIN 55,212-2 or the endogenous cannabinoid anandamide induced dose-related antinociception in the 55 degrees C warm-water tail-flick test. Pretreatment (24 h, i.c.v.) with pertussis toxin dose-dependently reduced the antinociceptive effect of delta9-THC (955 nmol), WIN 55,212-2 (30 nmol) and anandamide (135 nmol) (IC50 = 0.13, 5.5, and 0.32 nmol, respectively). In contrast, pretreatment (24 h, i.c.v.) with cholera toxin (0.1-3.0 mg) reduced the antinociception of WIN 55,212-2, had minimal effect on delta9-THC, and dose-dependently increased the antinociception of anandamide (ED50 = 0.50 nmol). These data suggest differences in the receptor-effector coupling of delta9-THC, WIN 55,212-2 and anandamide in supraspinal-induced antinociception in mice.
 ...
PMID:Differential cholera-toxin sensitivity of supraspinal antinociception induced by the cannabinoid agonists delta9-THC, WIN 55,212-2 and anandamide in mice. 1021 3

The CB1 subtype of the cannabinoid receptor is present on neurons in the brain and mediates the perceptual effects of Delta9-tetrahydrocannabinol and other cannabinoids. We found that cat cerebral arterial smooth muscle cells (VSMC) contain the protein for the CB1 receptor and express a cDNA that has >98% amino acid homology to the CB1 cDNA expressed in rat and human neurons. Activation of the CB1 cannabinoid receptor has been shown to decrease the opening of N-type voltage-gated Ca2+ channels in neurons through a pertussis toxin-sensitive GTP-binding protein. In the present study we tested the hypothesis that activation of the cannabinoid CB1 receptor in cerebral VSMC inhibits voltage-gated Ca2+ channels and results in cerebral vasodilation. The predominant Ca2+ current identified in cat cerebral VSMC is a voltage-gated, dihydropyridine-sensitive, L-type Ca2+ current. The cannabimimetic drug WIN-55,212-2 (10-100 nM) induced concentration-dependent inhibition of peak L-type Ca2+ current, which reached a maximum of 82 +/- 4% at 100 nM (n = 14). This effect was mimicked by the putative endogenous CB1-receptor agonist anandamide, which produced a concentration-related reduction of peak L-type Ca2+ current with a maximum inhibition (at 300 nM) of 39 +/- 4% (n = 12). The inhibitory effects of both ligands on peak L-type Ca2+ currents were abolished by pertussis toxin pretreatment and application of the CB1-receptor antagonist SR-141716A (100 nM, n = 5). Both WIN-55,212-2 and anandamide produced concentration-dependent relaxation of preconstricted cerebral arterial segments that was abolished by SR-141716A. These results indicate that the CB1 receptor is expressed in cat cerebral VSMC and that the cerebral vasculature is one of the targets for endogenous cannabinoids. These findings suggest that the CB1 receptor and its endogenous ligand may play a fundamental role in the regulation of cerebral arterial tone and reactivity by modulating the influx of Ca2+ through L-type Ca2+ channels.
 ...
PMID:Cannabinoid CB1 receptor of cat cerebral arterial muscle functions to inhibit L-type Ca2+ channel current. 1036 91

A physiological role for cannabinoids in the CNS is indicated by the presence of endogenous cannabinoids and cannabinoid receptors. However, the cellular mechanisms of cannabinoid actions in the CNS have yet to be fully defined. In the current study, we identified a novel action of cannabinoids to enhance intracellular Ca2+ responses in CNS neurons. Acute application of the cannabinoid receptor agonists R(+)-methanandamide, R(+)-WIN, and HU-210 (1-50 nM) dose-dependently enhanced the peak amplitude of the Ca2+ response elicited by stimulation of the NMDA subtype of glutamate receptors (NMDARs) in cerebellar granule neurons. The cannabinoid effect was blocked by the cannabinoid receptor antagonist SR141716A and the Gi/Go protein inhibitor pertussis toxin but was not mimicked by the inactive cannabinoid analog S(-)-WIN, indicating the involvement of cannabinoid receptors. In current-clamp studies neither R(+)-WIN nor R(+)-methanandamide altered the membrane response to NMDA or passive membrane properties of granule neurons, suggesting that NMDARs are not the primary sites of cannabinoid action. Additional Ca2+ imaging studies showed that cannabinoid enhancement of the Ca2+ signal to NMDA did not involve N-, P-, or L-type Ca2+ channels but was dependent on Ca2+ release from intracellular stores. Moreover, the phospholipase C inhibitor U-73122 and the inositol 1,4,5-trisphosphate (IP3) receptor antagonist xestospongin C blocked the cannabinoid effect, suggesting that the cannabinoid enhancement of NMDA-evoked Ca2+ signals results from enhanced release from IP3-sensitive Ca2+ stores. These data suggest that the CNS cannabinoid system could serve a critical modulatory role in CNS neurons through the regulation of intracellular Ca2+ signaling.
 ...
PMID:Cannabinoids enhance NMDA-elicited Ca2+ signals in cerebellar granule neurons in culture. 1051 96

1. The aim of the current study was to characterize which cannabinoid receptors, if any, are present on rat carotid artery smooth muscle. Additionally, the effects of cannabinoids on carotid artery tone, on cyclic AMP accumulation and on forskolin-induced relaxation were examined in the same tissue. 2. Stimulation of carotid arteries with forskolin (10 microM) significantly increased cyclic AMP accumulation, an effect that was inhibited in a concentration-dependent manner by the cannabinoid receptor agonist, methanandamide. 3. Similar inhibition was seen with the CB1 agonist HU-210 but this inhibition was not mimicked by the CB2 agonist, WIN 55,2212-2. 4. The inhibitory effect of methanandamide on cyclic AMP accumulation was prevented by incubation of the arteries with pertussis toxin and was significantly reduced by LY320135, a selective CB1 antagonist, but not by SR 144528, a CB2-selective antagonist. 5. Methanandamide failed to relax carotid arteries pre-contracted with phenylephrine, but inhibited forskolin-induced relaxation of these arteries. This functional inhibition of relaxation by methanandamide was inhibited by CB1-selective (LY320135 and SR 141716A), but not a CB2-selective antagonist (SR 144528). 6. These data demonstrate the presence of functional G protein-linked cannabinoid receptors of the CB1 subtype in the rat carotid artery, but show that these receptors inhibit cyclic AMP accumulation rather than cause relaxation.
 ...
PMID:Cannabinoid CB1 receptors fail to cause relaxation, but couple via Gi/Go to the inhibition of adenylyl cyclase in carotid artery smooth muscle. 1051 38

Cannabinoid (CB(1)) receptor activation produced differential effects on voltage-gated outward potassium currents in whole-cell recordings from cultured (7-15 days) rat hippocampal neurons. Voltage-dependent potassium currents A (I(A)) and D (I(D)) were isolated from a composite tetraethylammonium-insensitive current (I(comp)) by blockade with either 4-aminopyridine (500 microM) or dendrotoxin (2 microM) and subtraction of the residual I(A) from I(comp) to reveal I(D). The time constants of inactivation (tau) of I(A) and I(D) as determined in this manner were found to be quite different. The CB(1) agonist WIN 55,212-2 produced a 15- to 20-mV positive shift in voltage-dependent inactivation of I(A) and a simultaneous voltage-independent reduction in the amplitude of I(D) in the same neurons. The EC(50) value for the effect of WIN 55,212-2 on I(D) amplitude (13.9 nM) was slightly lower than the EC(50) value for its effect on I(A) voltage dependence (20.6 nM). Pretreatment with either the CB(1) antagonist SR141716A or pertussis toxin completely blocked the differential effects of WIN 55,212-2 on I(A) and I(D), whereas cellular dialysis with guanosine-5'-O-(3-thio)triphosphate mimicked the action of cannabinoids but blocked the action of simultaneously administered cannabinoid receptor ligands. Finally, the differential effects of cannabinoids on I(A) and I(D) were both shown to be mediated via the well documented cannabinoid receptor inhibition of adenylyl cyclase and subsequent modulation of cAMP and protein kinase. These actions are considered in terms of cAMP-mediated phosphorylation of separate I(A) and I(D) channels and the contribution of each to composite voltage-gated potassium currents in these cells.
 ...
PMID:Cannabinoid receptors differentially modulate potassium A and D currents in hippocampal neurons in culture. 1052 14

We tested the hypothesis that human CB1 cannabinoid receptors (hCB1) can sequester G(i/o)-proteins from a common pool and prevent other receptors from signaling. Human CB1 cannabinoid receptors were expressed in superior cervical ganglion (SCG) neurons by microinjection of hCB1 cDNA. Expression of hCB1 cannabinoid receptors abolished the Ca(2+) current inhibition by endogenous pertussis toxin-sensitive G(i/o)-coupled receptors for norepinephrine (NE) and somatostatin (SOM) but not by endogenous pertussis toxin-insensitive G(s)-coupled receptors for vasoactive intestinal polypeptide. Signaling by NE was rescued by expression of Galpha(oB), Gbeta(1), and Ggamma(3). Expression of mGluR2 metabotropic glutamate receptors, another pertussis toxin-sensitive G-protein-coupled receptor, had no effect on the signaling by NE or SOM. Some hCB1 receptors were constitutively active because the cannabinoid receptor inverse agonist SR 141617A enhanced the Ca(2+) current. Some hCB1 receptors also appear to be precoupled to G(i/o)-proteins because the cannabinoid agonist WIN 55,212-2 decreased the Ca(2+) current at a time when no G-proteins were available to couple to alpha(2)-adrenergic and somatostatin receptors. In SCG neurons microinjected with a lower concentration of hCB1 cDNA, the effect of SR 141716A was reduced, and the response to NE and SOM was partially restored. Subsequent to the application of SR 141716A, the Ca(2+) current inhibition by NE and SOM was abolished. These results suggest that both the active and inactive states of the hCB1 receptor can sequester G(i/o)-proteins from a common pool. Cannabinoid receptors thus have the potential to prevent other G(i/o)-coupled receptors from transducing their biological signals.
 ...
PMID:The CB1 cannabinoid receptor can sequester G-proteins, making them unavailable to couple to other receptors. 1053 31

The effect of delta9-tetrahydrocannabinol (THC), the major psycho-active component of marijuana, in human prostate cancer cells PC-3 was investigated. THC caused apoptosis in a dose-dependent manner. Morphological and biochemical changes induced by THC in prostate PC-3 cells shared the characteristics of an apoptotic phenomenon. First, loss of plasma membrane asymmetry determined by fluorescent anexin V binding. Second, presence of apoptotic bodies and nuclear fragmentation observed by DNA staining with 4',6-diamino-2-phenylindole (DAPI). Third, presence of typical 'ladder-patterned' DNA fragmentation. Central cannabinoid receptor expression was observed in PC-3 cells by immunofluorescence studies. However, several results indicated that the apoptotic effect was cannabinoid receptor-independent, such as lack of an effect of the potent cannabinoid agonist WIN 55,212-2, inability of cannabinoid antagonist AM 251 to prevent cellular death caused by THC and absence of an effect of pertussis toxin pre-treatment.
 ...
PMID:Delta9-tetrahydrocannabinol induces apoptosis in human prostate PC-3 cells via a receptor-independent mechanism. 1057 Sep 48

Cultured neurons from the thoracolumbar sympathetic chain of newborn mice are known to possess release-inhibiting alpha(2)-autoreceptors. The present study was carried out in a search for release-modulating heteroreceptors on these neurons. Primary cultures were preincubated with [(3)H]noradrenaline and then superfused and stimulated by single pulses, trains of 8 pulses at 100 Hz, or trains of 36 pulses at 3 Hz. The cholinergic agonist carbachol reduced the evoked overflow of tritium. Experiments with antagonists indicated that the inhibition was mediated by M(2) muscarinic receptors. The cannabinoid agonist WIN 55,212-2 reduced the evoked overflow of tritium through CB(1) receptors. Prostaglandin E(2), sulprostone, and somatostatin also caused presynaptic inhibition. The inhibitory effects of carbachol, WIN 55,212-2, prostaglandin E(2), and somatostatin were abolished (at the highest concentration of WIN 55, 212-2 almost abolished) by pretreatment of the cultures with pertussis toxin (250 ng/ml). Several drugs, including the beta(2)-adrenoceptor agonist salbutamol, opioid receptor agonists, neuropeptide Y, angiotensin II, and bradykinin, failed to change the evoked overflow of tritium. These results demonstrate a distinct pattern of presynaptic inhibitory heteroreceptors, all coupled to pertussis toxin-sensitive G proteins. The lack of operation of several presynaptic receptors known to exist in adult mice in situ may be due to the age of the (newborn) donor animals or to the culture conditions.
 ...
PMID:Electrically evoked release of [(3)H]noradrenaline from mouse cultured sympathetic neurons: release-modulating heteroreceptors. 1103 98


<< Previous 1 2 3 4 Next >>