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1.
The in vitro binding properties of the novel muscarinic antagonist [3H]AF-DX 116 were studied using a rapid filtration technique. Association and dissociation rates of [3H]AF-DX 116 binding were rapid at 25 degrees C (2.74 and 2.70 X 10(7) min-1 M-1 for K+1; 0.87 and 0.93 min-1 for k-1) but 20-40 times slower at 0-4 degrees C (0.13 and 0.096 X 10(7) min-1 M-1 for k+1; 0.031 and 0.022 min-1 for k-1 in cerebral cortical and cardiac membranes, respectively). Kinetic dissociation constants (Kds) were estimated to be 31.8 nM and 30.9 nM at 25 degrees C; 23.1 nM and 0-4 degrees C for the cerebral cortex and heart, respectively. In saturation studies, [3H]AF-DX 116 labeled 29 percent of the total [3H](-)QNB binding sites in the cerebral cortical membranes and 87 percent in the cardiac membranes, with Kd values of 28.9 nM and 17.9 nM, respectively. Muscarinic antagonists inhibited [3H]AF-DX 116 binding in a rank order of potency of atropine greater than dexetimide greater than AF-DX 116 greater than PZ greater than levetimide in both tissues. Except for PZ/[3H]AF-DX 116 and AF-DX 116/[3H]AF-DX 116 in the cerebral cortex, all the antagonist competition curves had Hill coefficients close to one. Carbachol and oxotremorine produced shallow inhibition curves against [3H]AF-DX 116 binding in both tissues. Regional distribution studies with [3H](-)QNB, [3H]PZ and [3H]AF-DX 116 showed that most of the muscarinic receptors in the cerebral cortex, hippocampus, nucleus accumbens and corpus striatum are of the M1 subtype while those in the brainstem, cerebellum and other lower brain regions are of the M2 subtype. These results indicate that [3H]AF-DX 116 is a useful probe for the study of heterogeneity of muscarinic cholinergic receptors. 相似文献
2.
Hormonal regulation of myosin heavy chain and alpha-actin gene expression in cultured fetal rat heart myocytes 总被引:8,自引:0,他引:8
T A Gustafson J J Bahl B E Markham W R Roeske E Morkin 《The Journal of biological chemistry》1987,262(27):13316-13322
Thyroid hormone regulates the expression of ventricular myosin isoenzymes by causing an accumulation of alpha-myosin heavy chain (MHC) mRNA and inhibiting expression of beta-MHC mRNA. However, the mechanism of thyroid hormone action has been difficult to examine in vivo because of its diverse actions. Accordingly, hormonal control of expression of six MHC isoform mRNAs and cardiac and skeletal alpha-actin mRNAs was studied in primary cultures of fetal rat heart myocytes grown in defined medium. The results indicate that in the absence of thyroid hormone, cultured heart cells express predominantly beta-MHC and cardiac alpha-actin mRNAs. Addition of 3,5,3'-triiodo-L-thyronine (T3) caused a rapid induction of alpha-MHC mRNA and decreased beta-MHC mRNA levels without affecting the skeletal muscle MHC mRNAs. There was an almost parallel change in the myosin isoenzymes. Cardiac alpha-actin mRNA levels were transiently increased by T3 treatment, but skeletal alpha-actin was unaffected. Elimination of insulin and epithelial growth factor from the medium did not alter the effects of T3 on cardiac MHC mRNA expression. Addition of various adrenergic agents to the medium had no appreciable effect on cardiac MHC mRNA expression despite the presence of functionally coupled alpha- and beta-adrenergic receptors. Addition of steroid hormones, muscarinic agents, and glucagon to the medium also had no effect. Thus, under defined conditions, T3 is able to regulate MHC gene expression at a pretranslational level without the need for other exogenous factors. 相似文献
3.
C. B. Osmond J. A. M. Holtum M. H. O'Leary C. Roeske O. C. Wong R. E. Summons P. N. Avadhani 《Planta》1988,175(2):184-192
The labeling patterns in malic acid from dark 13CO2 fixation in seven species of succulent plants with Crassulacean acid metabolism were analysed by gas chromatography-mass spectrometry and 13C-nuclear magnetic resonance spectrometry. Only singly labeled malic-acid molecules were detected and on the average, after 12–14 h dark 13CO2 fixation the ratio of [4-13C] to [1-13C] label was 2:1. However the 4-C carboxyl contained from 72 to 50% of the label depending on species and temperature. The 13C enrichment of malate and fumarate was similar. These data confirm those of W. Cockburn and A. McAuley (1975, Plant Physiol. 55, 87–89) and indicate fumarase randomization is responsible for movement of label to 1-C malic acid following carboxylation of phosphoenolpyruvate. The extent of randomization may depend on time and on the balance of malic-acid fluxes between mitochondria and vacuoles. The ratio of labeling in 4-C to 1-C of malic acid which accumulated following 13CO2 fixation in the dark did not change during deacidification in the light and no doubly-labeled molecules of malic acid were detected. These results indicate that further fumarase randomization does not occur in the light, and futile cycling of decarboxylation products of [13C] malic acid (13CO2 or [1-13C]pyruvate) through phosphoenolpyruvate carboxylase does not occur, presumably because malic acid inhibits this enzyme in the light in vivo. Short-term exposure to 13CO2 in the light after deacidification leads to the synthesis of singly and multiply labeled malic acid in these species, as observed by E.W. Ritz et al. (1986, Planta 167, 284–291). In the shortest times, only singly-labeled [4-13C]malate was detected but this may be a consequence of the higher intensity and better detection statistics of this ion cluster during mass spectrometry. We conclude that both phosphoenolpyruvate carboxylase (EC 4.1.1.32) and ribulose-1,5-biphosphate carboxylase (EC 4.1.1.39) are active at this time.Abbreviations CAM
Crassulacean acid metabolism
- GCMS
gas chromatography-mass spectrometry
- MS
mass spectrometry
- NMR
nuclear magnetic resonance spectrometry
- PEP
phosphoenolpyruvate
- RuBP
ribulose 1,5-bisphosphate 相似文献
4.
5.
A highly conserved nuclear gene for low-level phylogenetics: elongation factor-1 alpha recovers morphology-based tree for heliothine moths 总被引:8,自引:2,他引:6
Cho S; Mitchell A; Regier JC; Mitter C; Poole RW; Friedlander TP; Zhao S 《Molecular biology and evolution》1995,12(4):650-656
Molecular systematists need increased access to nuclear genes. Highly
conserved, low copy number protein-encoding nuclear genes have attractive
features for phylogenetic inference but have heretofore been applied mostly
to very ancient divergences. By virtue of their synonymous substitutions,
such genes should contain a wealth of information about lower-level
taxonomic relationships as well, with the advantage that amino acid
conservatism makes both alignment and primer definition straightforward. We
tested this postulate for the elongation factor-1 alpha (EF-1 alpha) gene
in the noctuid moth subfamily Heliothinae, which has probably diversified
since the middle Tertiary. We sequenced 1,240 bp in 18 taxa representing
heliothine groupings strongly supported by previous morphological and
allozyme studies. The single most parsimonious gene tree and the
neighbor-joining tree for all nucleotides show almost complete concordance
with the morphological tree. Homoplasy and pairwise divergence levels are
low, transition/transversion ratios are high, and phylogenetic information
is spread evenly across gene regions. The EF-1 alpha gene and presumably
other highly conserved genes hold much promise for phylogenetics of
Tertiary age eukaryote groups.
相似文献
6.
Cardiac muscarinic cholinergic receptors. Biochemical identification and characterization 总被引:25,自引:0,他引:25
J Z Fields W R Roeske E Morkin H I Yamamura 《The Journal of biological chemistry》1978,253(9):3251-3258
7.
H B Wei W R Roeske J Lai F Wanibuchi K Hidaka S Usuda H I Yamamura 《Life sciences》1992,50(5):355-363
To investigate the pharmacological effect of a novel compound YM796, we performed radioligand binding experiments and correlative biochemical experiments using the transfected murine fibroblast B82 cells which expressed the m1 and m2 muscarinic receptor genes (cloned cell lines designated as LK3-3 and M2LKB2-2, respectively). [3H](-)methyl-3-quinuclidinyl benzilate [( 3H](-)MQNB) binding in these transfected cell lines was inhibited by different optical isomers of YM796 and other muscarinic drugs, atropine, pirenzepine, AF-DX 116, as well as selected agonists. (-)YM796, (+)YM796 and (+/-)YM796 inhibited [3H](-)MQNB binding in LK3-3 cells with Ki values of 16.4 microM, 30.1 microM and 21.8 microM and in M2LKB2-2 cells with Ki values of 52.0 microM, 108 microM and 77.1 microM, respectively. From functional assays we found the two isomers, (-)YM796 and (+)YM796 had different intrinsic activities for the M1 and M2 muscarinic receptors. (-)YM796 revealed agonistic activity: stimulation of [3H]IP1 accumulation in LK3-3 cells with an EC50 value of 26.5 microM, which was less efficacious (the Emax value was 5.6 times basal) than carbachol, a full agonist (the Emax value was 17.2 times basal). Interestingly, (-)YM796 did not show significant inhibition of cAMP formation in M2LKB2-2 cells except at extremely high concentrations (greater than 1mM). (+)YM796 exhibited no significant efficacy for the M1 and M2 muscarinic receptors. These results suggest that (-)YM796 represents a muscarinic partial agonist with functional selectivity for the M1 muscarinic receptors whereas (+)YM796 shows no efficacy for either M1 or M2 muscarinic receptors in these transfected cells. 相似文献
8.
The interaction of propyl β-carboline-3-carboxylate (PCC) with benzodiazepine receptors in the cerebral cortex of the rat was investigated by direct measurements of [3H]PCC binding and by competitive inhibition of [3H]flunitrazepam (FLU) binding. Initial experiments showed that [3H]PCC binding exhibited characteristics of saturability, stereospecificity and a pharmacological specificity remarkably similar to that of [3H]FLU binding. Analysis of [3H]PCC binding isotherms and PCC/[3H]PCC competition curves revealed the presence of a small population of super high affinity PCC binding sites (KSH = 30–100 pM) which represents approximately 3–6% of the total sites. When measured by competitive inhibition of [3H]FLU binding, receptor occupancy by PCC was generally consistent with that determined by direct measurements of [3H]PCC binding. Analysis of the PCC/[3H]FLU competition curve revealed the presence of two major populations of high and low affinity PCC binding sites with dissociation constants of 0.54 and 10 nM and relative abundances of 52 and 45%, respectively. Collectively, the results of the [3H]PCC binding isotherm, PCC/[3H]PCC competition curve and PCC/[3H]FLU competition curve are internally consistent when rationalized in terms of three populations of benzodiazepine receptors - super high, high, and low affinity - each having different affinities for PCC and equal affinity for FLU. The effects of γ-aminobutyric acid (GABA) on PCC and FLU binding were investigated, and it was observed that GABA enhanced the binding of FLU to the various receptor subtypes whereas no significant effect of GABA on the binding of PCC was detected. 相似文献
9.
Frederick J. Ehlert Yvon Dumont William R. Roeske Henry I. Yamamura 《Life sciences》1980,26(12):961-967
Muscarinic receptor binding was measured in rat forebrain preparations using the muscarinic agonist, [3H]cis methyldioxolane ([3H]CD). The results of equilibrium binding studies using [3H]CD concentrations between 0.5–64 nM showed that [3H]CD binding did not saturate in this concentration range, although the binding isotherm was concave downward. Nonlinear regression analysis of the binding data revealed the presence of two populations of muscarinic receptors having dissociation constants of 1.83 and 123 nM and binding capacities of 85 and 1320 fmol/mg protein, respectively. Competitive inhibition experiments showed that [3H]CD binding was readily displaced by several muscarinic agonists and antagonists. The stereospecificity of [3H]CD binding was demonstrated in competitive inhibition experiments using the stereoisomers of benzetimide and acetyl-β-methylcholine. Dexetimide was 10,000 times more potent than levetimide and l-acetyl-β-methylcholine was 520 times more potent than d-acetyl-β-methylcholine. A variety of nonmuscarinic cholinergic drugs were not effective at inhibiting [3H]CD binding at a concentration of 10 μM. 相似文献
10.
Alterations in central and peripheral adrenergic receptors in deoxycorticosterone/salt hypertensive rats 总被引:4,自引:0,他引:4
The treatment of uninephrectomized rats with deoxycorticosterone (DOCA) and salt for 6 weeks caused a significant systolic hypertension and cardiac and renal hypertrophy. There was a significant decrease in the density of cardiac α1- and β-, and renal α1-adrenoceptors in DOCA/salt hypertensive rats, as compared to uninephrectomized salt loaded control rats. In contrast, the cerebral cortex, corpus striatum, hippocampus and hypothalamus/thalamus of hypertensive rats showed a significant increase in adrenoceptor binding in these hypertensive rats. In contrast, muscarinic cholinergic receptors and [3H]yohimbine binding sites were not altered in most tissues of the hypertensive rats. The present study suggests an important role for central and peripheral α1- and β-adrenoceptors in the pathogenesis of hypertension. 相似文献