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

Clonidine and cirazoline bind with high affinity to a nonadrenergic site in the brain stem, the so-called imidazoline I1 receptor. Our aim was to determine the mechanism by which these receptors act and their possible linkage to signal-transducing heterotrimeric G-proteins. We examined the effects of clonidine and cirazoline on PC-12 cells, a neuronal cell line that is reported to possess the I1 site and have no alpha 2-adrenoceptors. In undifferentiated PC-12 cells loaded with the Ca2+ indicator dye fura-2, clonidine and cirazoline (10-100 microM) inhibited the increase in [Ca2+]i produced by nicotine (10 microM). This inhibition was not reversed by yohimbine (100 microM), and adrenaline and BHT 920 were ineffective at 100 microM. This effect was not inhibited by pretreatment with pertussis toxin (24 hours, 100 ng/ml) and not modulated by pretreatment with IBMX (100 microM). The nicotine-induced increase in [Ca2+]i is apparently due to Ca2+ entering via the intrinsic ion channel of the nicotinic acetylcholine receptor. Clonidine and cirazoline inhibited the inward current produced by nicotine (10 microM) as measured by the whole cell patch-clamp technique in differentiated PC-12 cells, recorded at a holding potential of -60 mV. In agreement with the results found with fura-2, inhibition of inward current was concentration dependent and not blocked by yohimbine (100 microM) or mimicked by adrenaline (100 microM). Pretreatment of PC-12 cells with pertussis toxin or infusion of GDP-beta-S (2 mM) via the patch pipette did not alter the inhibition of the nicotine-induced inward current by clonidine or cirazoline. Clonidine and cirazoline, but not adrenaline, displayed [3H]phencyclidine from Torpedo electroplaque membranes enriched in nicotinic acetylcholine receptors in a concentration-dependent manner (10-100 microM). Taken together, these results suggest that clonidine and cirazoline inhibit Na+ and Ca2+ entry through the nicotinic acetylcholine receptor via a nonadrenergic mechanism that is independent of G-proteins and cyclic nucleotides, presumably by direct blockade of the intrinsic ion channel of the nicotinic acetylcholine receptor.
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PMID:Clonidine and cirazoline inhibit activation of nicotinic channels in PC-12 cells. 754 85

A desensitizing protocol to i.c.v. substance P (SP) (from 0.1-10 nmol x 2 at 25-min interval) diminished the supraspinal mu-mediated antinociceptive activity of morphine, D-Ala2-N-MePhe4-Gly-ol5-enkephalin (DAMGO), beta-endorphin-(1-31), D-Ala2-D-Leu5-enkephalin and of the alpha-2 agonist clonidine, whereas the activity of the highly selective delta ligands [D-Pen2,5]-enkephalin and [D-Ala2]-Deltorphin II remained unchanged. This effect was noncompetitive as the slopes for the antinociceptive dose-response curves diminished after SP pretreatment. The antagonism was evident within a few hours after SP and lasted longer than 15 days. The N-acetyl derivative of beta-endorphin-(1-31) (1 pmol) increased the antinociceptive response of DAMGO, D-Ala2-D-Leu5-enkephalin and clonidine, but not of morphine, in SP-pretreated mice. ED80 values of opioid agonists or naltrexone did not prevent SP from reducing the antinociceptive activity of opioids and clonidine. The effect of N-acetyl beta-endorphin-(1-31) was transitory and disappeared within 48 hr, after this period the long-lasting antagonism of SP was revealed. Clonidine (150 nmol) also enhanced opioid antinociception in SP-treated mice. This effect was reversed by the alpha-2 antagonist yohimbine (50 nmol) when given 10 min before clonidine. In mice undergoing treatment with pertussis toxin (0.5 micrograms i.c.v.), an agent that impairs the function of GTP-binding regulatory proteins (Gi/Go), the SP desensitizing protocol did not reduce further the antinociception of DAMGO or morphine. These results suggest a modulatory role for the SP system and the neuropeptide N-acetyl beta-endorphin-(1-31) upon mu and alpha-2 but not delta-mediated supraspinal antinociception in mice.
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PMID:N-acetyl beta-endorphin-(1-31) and substance P regulate the supraspinal antinociception mediated by mu opioid and alpha-2 adrenoceptors but not by delta opioid receptors in the mouse. 768 46

Agents that elevate intracellular cyclic AMP (cAMP) have been found to enhance the synaptic discharge of norepinephrine (NE) from sympathetic nerve terminals in the rabbit iris-ciliary body and other peripheral tissues. We explored the hypothesis that prejunctional alpha 2-adrenergic receptors that mediate feedback inhibition of NE release may be coupled to adenylyl cyclase inhibition. To indirectly monitor cAMP changes in sympathetic axon terminals, we analyzed the cAMP-mediated activation of tyrosine hydroxylase, a sympathetic marker protein that undergoes acute phosphorylation and activation by cAMP-dependent protein kinase A. Tyrosine hydroxylase activity was assayed in situ by incubation of rabbit iris-ciliary body tissue segments in buffered Krebs-Ringer solution containing the substrate tyrosine (100 microM) and the DOPA decarboxylase inhibitor brocresine (30 microM). Intraneuronal DOPA accumulation was quantified by HPLC with electrochemical detection. Tyrosine hydroxylase activity was increased approximately 2 fold by incubation with forskolin (10 microM) plus IBMX (0.5 mM) or with 8-Bromo-cAMP (3 mM). Simultaneous addition of the alpha 2-adrenergic agonist clonidine (1 microM) attenuated the response to forskolin/IBMX, but had no effect on the response to 8-Br-cAMP. Clonidine-mediated inhibition of the forskolin/IBMX response was abolished by treatment of tissues with N-ethylmaleimide (NEM), an alkylating agent that inactivates pertussis toxin-sensitive G proteins (Gi) that couple receptors to adenylyl cyclase inhibition. These findings suggest that prejunctional alpha 2-adrenoceptors in the rabbit iris-ciliary body are negatively coupled to adenylyl cyclase. This mechanism may contribute to autofeedback regulation of NE biosynthesis and release.
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PMID:Prejunctional alpha 2-adrenoceptors and adenylyl cyclase regulation in the rabbit iris-ciliary body. 771 5

alpha 2-Adrenoceptor agonists and somatostatin (SS) exert opposite effects on the spike discharge of pyramidal and granule cells in the rat hippocampus. We studied whether clonidine, an alpha 2-adrenoceptor agonist, and yohimbine, an alpha 2-adrenoceptor antagonist, can modulate somatostatin-like immunoreactivity (SSLI) levels, binding of 125I-Tyr11-somatostatin (125I-Tyr11-SS) to its specific receptors, SS-inhibited adenylyl cyclase (AC) activity, and the guanine-nucleotide binding regulatory proteins Gi and G(o) in the rat hippocampus. Clonidine (1 mg/kg, intraperitoneally (IP) or yohimbine (5 mg/kg, IP) injected at both 10 and 16 hours before decapitation did not affect SSLI content in the hippocampus. Clonidine administration decreased the number of specific SS receptors and increased the apparent affinity in hippocampal membranes. This change in SS binding was not the result of a direct effect of clonidine on these receptors because no effect in binding was produced by high concentrations of clonidine (10(-5) M) when added in vitro. Pretreatment with yohimbine prevented the clonidine-induced in SS binding. Yohimbine alone produced a significant increase in the number of 125I-Tyr11-SS receptors and a decrease in its apparent affinity. Clonidine decreased the ADP-ribosylation of a 41- and a 39-kDa G-protein by pertussis toxin (PTX), whereas yohimbine had no effect on the PTX-catalyzed ADP-ribosylation. No significant differences were seen for the basal or for the forskolin (FK)-stimulated AC enzyme activities in the control, clonidine- and/or yohimbine-treated groups. Somatostatin caused a significantly lower inhibition in AC activity in hippocampal membranes of clonidine-treated rats, whereas yohimbine led to an opposite effect.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Alpha-2 adrenoceptors modulate the somatostatinergic system and G protein levels in the rat hippocampus. 776 86

We investigated the acute and chronic effects of alpha 2-adrenoceptor and muscarinic receptor agonists on dihydropyridine-sensitive voltage-dependent Ca2+ channels in spinal cord-dorsal root ganglion cocultures. Clonidine and oxotremorine inhibited the voltage-dependent Ca2+ influx (42 +/- 2% and 35 +/- 6% with 100 microM, respectively). The respective antagonists, yohimbine and atropine, abolished these effects. Pertussis toxin attenuated the inhibitory effects of clonidine and oxotremorine on Ca2+ influx, demonstrating involvement of G proteins in the transduction process. Chronic treatment with clonidine or oxotremorine desensitized the Ca2+ channel response to the agonist applied as well as to the other receptor agonist (heterologous desensitization). Such treatment with clonidine or oxotremorine decreased the pertussis toxin-catalyzed ADP-ribosylation of Gi alpha and G(o) alpha subunits, an effect which could be largely reversed by the detergent Lubrol PX. Yohimbine and atropine blocked the effects of clonidine or oxotremorine on pertussis toxin-catalyzed ADP-ribosylation. Results suggest that alpha 2-adrenoceptor and muscarinic receptors couple to the dihydropyridine-sensitive voltage-dependent Ca2+ channels via pertussis toxin-sensitive G proteins. Chronic agonist treatment leads to heterologous desensitization and to a reduced capacity of Gi and G(o) to undergo pertussis toxin-catalyzed ADP-ribosylation.
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PMID:Heterologous desensitization and reduced G protein ADP-ribosylation following exposure to alpha 2-adrenoceptor and muscarinic receptor agonists. 809

1. The modulatory effect of alpha 2 adrenoceptor on the taurine response was investigated in substantia nigra (SN) neurons acutely dissociated from the rat using a nystatin perforated-patch recording mode under voltage-clamp conditions. 2. Complete cross-desensitization was observed between 10(-3) M glycine and 3 x 10(-3) M taurine-induced currents. Both currents were antagonized by 10(-6) M strychnine, thus indicating that taurine acts on strychnine-sensitive glycine receptor on the SN neurons. 3. The simultaneous application of norepinephrine (NE) with prazosin (10(-5) M) and propranolol (10(-5) M) potentiated the taurine response (Itau) in an NE concentration-dependent manner at a holding potential (VH) of -40 mV. Clonidine mimicked the NE effect on the Itau, thus indicating the involvement of alpha 2 adrenoceptor activation in the potentiation of Itau. 4. Alpha 2 adrenoceptor activation by NE with prazosin and propranolol significantly potentiated the peak amplitude of Itau without shifting the taurine concentration-response relationships either to left or right side. The respective concentrations of taurine for the threshold, half maximal and maximal responses in the presence of 10(-4) M NE with prazosin (10(-5) M) and propranolol (10(-5) M) were 3 x 10(-5) M, 3.1 x 10(-4) M, and 3 x 10(-3) M. The same concentrations in the absence of NE were 3 x 10(-5) M, 3.2 x 10(-4) M, and 3 x 10(-3) M, respectively. 5. The reversal potentials of Itau with and without NE were very close to the theoretical Cl- equilibrium potential, thus indicating that the potentiation of Itau by alpha 2 adrenoceptor activation was due to an increase in the taurine-induced Cl- currents. 6. Forskolin (3 x 10(-5) M) and isobutylmethylxanthine (3 x 10(-5) M) suppressed the peak amplitude of Itau. In the presence of dibutyryl cyclic AMP (10(-4) M), which also suppressed Itau, alpha 2 adrenoceptor activation failed to potentiate Itau. 7. N-[2(methylamino)ethyl]-5-isoquinoline sulfonamide dihydrochloride (H-89) mimicked the effect of alpha 2 adrenoceptor activation on Itau. In addition, the potentiation of Itau by alpha 2 adrenoceptor was not observed in the presence of 10(-6) M H-89. 8. The treatment of SN neurons with pertussis toxin (500 ng/ ml) for 18 h completely abolished the facilitatory effect of alpha 2 adrenoceptor on Itau. 9. These results suggest that the activation of alpha 2 adrenoceptor coupled with IAP-sensitive GTP binding protein decreases the intracellular cyclic AMP and cyclic AMP-dependent protein kinase activity, thus resulting in the potentiation of glycine receptor-mediated taurine response in rat SN neurons.
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PMID:Alpha 2 adrenoceptor potentiates glycine receptor-mediated taurine response through protein kinase A in rat substantia nigra neurons. 889 17

We measured agonist-stimulated binding of the stable GTP-analog guanosine-5'-O-(3-[35S]thiotriphosphate) ([35S]GTPgammaS) as a functional assay to monitor G-protein activation by recombinant human alpha2-adrenoceptor subtypes alpha2A, alpha2B and alpha2C. (-)-Noradrenaline was a full agonist in all receptors. Dexmedetomidine, UK14,304, clonidine and oxymetazoline showed subtype-selectivity in efficacy. Dexmedetomidine was a full agonist at alpha2B and a partial agonist at alpha2A; UK14,304 was a full agonist at alpha2A and a partial agonist at alpha2B. Clonidine and oxymetazoline were weak partial agonists at the alpha2B-subtype, but appeared inactive at alpha2A and alpha2C. The [35S]GTPgammaS binding assay provides functional information on pertussis toxin-sensitive G-protein activation, complementing radioligand binding assays and conventional second messenger assays.
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PMID:Subtype-specific stimulation of [35S]GTPgammaS binding by recombinant alpha2-adrenoceptors. 976 42

The agonist profiles for Ca++ elevations mediated by the human alpha-2 adrenoceptor subtypes alpha-2A, alpha-2B and alpha-2C were compared in the clones of Chinese hamster ovary cells expressing comparable numbers of receptors. No difference was seen between the different clones with respect to the maximum Ca++ mobilizations or the concentrations producing half-maximal stimulation in response to noradrenaline. Ca++ elevations were sensitive to phospholipase C inhibitor U-73122 (1-[6-([17beta]-3-methoxyestra-1,3, 5[10]-trien-17-yl)aminohexyl]-1H-pyrrole-2,5-dione) and pertussis toxin-pretreatment. Although noradrenaline was equally potent and active in all the clones, marked differences in the response to the other agonists were seen. UK14,304 (5-bromo-N-[4, 5-dihydro-1H-imidazol-2-yl]-6-quinoxalinamine) was a full agonist (when compared to noradrenaline) for alpha-2A and alpha-2C, D-medetomidine ([+]-[S]-[4-(1-[2, 3-dimethylphenyl]ethyl)-1H-imidazole]HCl) was a full agonist for alpha-2B and alpha-2C and oxymetazoline (3-[(4, 5-dihydro-1H-imidazol-2-yl-)methyl]-6-[1,1-dimethylethyl]-2, 4-dimethylphenol HCl) was a full agonist only for alpha-2B receptors. Clonidine (2-[2,6-dichloroaniline]-2-imidazoline HCl) was a partial agonist in all the cases; almost no response to this ligand was obtained in the alpha-2B-expressing cells. When the Ca++ responses are compared to the previously published results on cAMP inhibition in Chinese hamster ovary cells, clonidine seems to be significantly less efficacious in elevating Ca++ than in decreasing cAMP.
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PMID:Ligand- and subtype-selective coupling of human alpha-2 adrenoceptors to Ca++ elevation in Chinese hamster ovary cells. 980 94

The effect of noradrenaline on the glycine response was investigated in neurons acutely dissociated from the rat sacral dorsal commissural nucleus using nystatin perforated patch recording configuration under voltage-clamp conditions. Noradrenaline reversibly potentiated the 10(-5)M glycine-induced Cl- current in a concentration-dependent manner. Single channel recordings in a cell-attached mode revealed that noradrenaline decreased the closing time of the glycine-activated channel activity. Noradrenaline neither changed the reversal potential of the glycine response nor affected the affinity of glycine to its receptor. Clonidine mimicked and yohimbine blocked the noradrenaline action on glycine response. N-[2(methylamino)ethyl]-5-isoquinoline sulfonamide dihydrochloride, protein kinase A inhibitor, mimicked the effect of noradrenaline on glycine response. Noradrenaline failed to affect the glycine response in the presence of these intracellular cyclic AMP and protein kinase A modulators. However, noradrenaline further enhanced the glycine response even in the presence of phorbol-12-myristate-13-acetate and chelerythrine, a protein kinase C inhibitor. Pertussis toxin treatment for 6-8 h blocked the noradrenaline facilitatory effect on the glycine response. In addition, noradrenaline potentiated the strychnine-sensitive postsynaptic currents evoked in a slice preparation of sacral dorsal commissural nucleus. These results suggest that the activation of alpha2-adrenoceptor by noradrenaline coupled with pertussis toxin-sensitive G-proteins reduces intracellular cyclic AMP formation through the inhibition of adenyl cyclase. The reduction of cyclic AMP decreases the protein kinase A activity, thus resulting in the potentiation of the glycinergic inputs to the sacral dorsal commissural neurons. It is thus feasible that the noradrenergic input to the sacral dorsal commissural nucleus modulates such nociceptive signals as pain by intracellular enhancing the glycine response.
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PMID:Alpha2-adrenoceptor-mediated enhancement of glycine response in rat sacral dorsal commissural neurons. 1005 Dec 15

The alpha2-adrenoceptor mediating inhibition of forskolin-stimulated cyclic AMP accumulation in human neuroblastoma SH-SY5Y cells was further characterized. The alpha2-adrenoceptor agonists, UK 14,304 (5-bromo-6-(2-imidazolin-2-ylamino)quinoxaline), oxymetazoline, guanfacine, (-)-noradrenaline and clonidine concentration-dependently decreased cyclic AMP accumulation in this cell line (Emax ca. 50% inhibition). Agonist pEC50 values ranged between 6.7 and 7.8. Clonidine was a partial agonist. The effects of UK 14,304 were blocked after a pertussis toxin treatment. The concentration-response curves of UK 14,304 were shifted to the right in a parallel manner by the following antagonists (mean pK(B) values): yohimbine (8.17), idazoxan (7.63), prazosin (6.66), 2-[2-(4-(2-methoxyphenyl)piperazin-1-yl)ethyl]-4,4-dimethyl-1,3-(2 H,4H) isoquinolindione (ARC 239; 7.12) and 2-(2,6-dimethoxyphenoxyethyl)aminomethyl-1,4-benzodioxane (WB-4101; 8.12). The relatively high pKB values of prazosin and ARC 239 point to a non-alpha2A-adrenoceptor-mediated effect. The relatively high pK(B) value of WB-4101 further characterizes the alpha2-adrenoceptor in SH-SY5Y cells as being of the alpha2C subtype. The analysis of the expression of alpha2-adrenoceptor subtypes by reverse transcriptase-polymerase chain reaction (RT-PCR) revealed the exclusive presence of alpha2C-adrenoceptor mRNA in SH-SY5Y cells. We propose that inhibition of forskolin-stimulated cAMP accumulation in SH-SY5Y cells be used as a functional model of human, native alpha2C-adrenoceptors.
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PMID:Functional alpha2C-adrenoceptors in human neuroblastoma SH-SY5Y cells. 1037 21


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