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Half-maximal Response (half-maximal + response)
Selected AbstractsThe molecular receptive range of an olfactory receptor in vivo (Drosophila melanogaster Or22a)DEVELOPMENTAL NEUROBIOLOGY, Issue 14 2006Daniela Pelz Abstract Understanding how odors are coded within an olfactory system requires knowledge about its input. This is constituted by the molecular receptive ranges (MRR) of olfactory sensory neurons that converge in the glomeruli of the olfactory bulb (vertebrates) or the antennal lobe (AL, insects). Aiming at a comprehensive characterization of MRRs in Drosophila melanogaster we measured odor-evoked calcium responses in olfactory sensory neurons that express the olfactory receptor Or22a. We used an automated stimulus application system to screen [Ca2+] responses to 104 odors both in the antenna (sensory transduction) and in the AL (neuronal transmission). At 10,2 (vol/vol) dilution, 39 odors elicited at least a half-maximal response. For these odorants we established dose-response relationships over their entire dynamic range. We tested 15 additional chemicals that are structurally related to the most efficient odors. Ethyl hexanoate and methyl hexanoate were the best stimuli, eliciting consistent responses at dilutions as low as 10,9. Two substances led to calcium decrease, suggesting that Or22a might be constitutively active, and that these substances might act as inverse agonists, reminiscent of G-protein coupled receptors. There was no difference between the antennal and the AL MRR. Furthermore we show that Or22a has a broad yet selective MRR, and must be functionally described both as a specialist and a generalist. Both these descriptions are ecologically relevant. Given that adult Drosophila use approximately 43 ORs, a complete description of all MRRs appears now in reach. © 2006 Wiley Periodicals, Inc. J Neurobiol, 2006 [source] A novel inducible tyrosine kinase receptor to regulate signal transduction and neurite outgrowthJOURNAL OF NEUROSCIENCE RESEARCH, Issue 12 2009Ronald W. Alfa Abstract Nervous system growth factor gene delivery can promote axonal growth and prevent cell death in animal models of CNS trauma and neurodegenerative diseases. The ability to regulate growth factor expression or signaling pathways downstream from growth factor receptors remains a desirable goal for in vivo gene transfer. To achieve precise pharmacological modulation of neurotrophin activity, we have generated a chimeric trkA receptor (ItrkA) by fusing the entire intracellular domain of the trkA high-affinity NGF receptor to two intracellular, modified FK506 binding domains for the synthetic small molecule dimerization ligand AP20187. Rat PC12 cells were transduced with lentiviral vectors containing ItrkA and green fluorescent protein (GFP; via an internal ribosome entry site). Treatment of ItrkA-expressing PC12 cells with AP20187 induced neurite outgrowth and differentiation in a time- and dose-dependent fashion, with a half-maximal response at a concentration of 1 nM AP20187. Seventy percent of cells responded to AP20187 by day 3. Western blots demonstrated that AP20187 treatment resulted in phosphorylation of Erk1/2 and Akt in ItrkA-transduced PC12 cells but not in nontransduced, naïve cells. Phosphorylation levels were comparable to levels obtained with 50 ng/ml nerve growth factor (NGF). In addition, ItrkA lentiviral transduction of primary E15 dorsal root ganglion neurons significantly increased neurite growth three- to fourfold in the presence of AP20187 compared with control GFP transduced and naïve neurons. These results demonstrate that small ligand-induced dimerization of the intracellular domain of trkA can efficiently simulate the biological activity of NGF and provide a means to regulate intracellular neurotrophin receptor signaling. © 2009 Wiley-Liss, Inc. [source] Threshold analysis of selected dose-response data for endocrine active chemicals,APMIS, Issue 3 2001Robert M. Blair Using a biologically relevant mathematical model, the Michaelis-Menten equation, we examined published data from endocrine active chemicals for evidence of no-threshold dose-response curves. Data were fit to a modified Michaelis-Menten equation which accounted for total background response. Subsequently, the data sets were analyzed using non-linear regression in order to estimate the four parameters of interest (non-hormone controlled background (Bnh), maximum response (Rmax), endogenous hormone level (D0), and the dose at which a half-maximal response was observed (ED50)) and to determine the fit to the fully modified Michaelis-Menten equation. Subsequently, response data were adjusted to account for Bnh and then normalized to Rmax, while dose data were adjusted to account for D0 and then normalized to the ED50. This data set was combined into a single, composite data set and fit to the fully modified Michaelis-Menten equation. We examined 31 data sets (24 endpoints) from studies on 9 different chemical/hormone treatments. Twenty-six of the data sets fit the modified Michaelis-Menten equation with high multiple correlation coefficients (r>0.90). The normalized data demonstrated a good fit to the modified Michaelis-Menten equation. These results indicate that a variety of biological responses fit the modified Michaelis-Menten equation, which does not have a threshold dose term. [source] Gq/11 and Gi/o activation profiles in CHO cells expressing human muscarinic acetylcholine receptors: dependence on agonist as well as receptor-subtypeBRITISH JOURNAL OF PHARMACOLOGY, Issue 4 2001Elizabeth C Akam Profiles of G protein activation have been assessed using a [35S]-GTP,S binding/immunoprecipitation strategy in Chinese hamster ovary cells expressing either M1, M2, M3 or M4 muscarinic acetylcholine (mACh) receptor subtypes, where expression levels of M1 and M3, or M2 and M4 receptors were approximately equal. Maximal [35S]-GTP,S binding to Gq/11, stimulated by M1/M3 receptors, or Gi1 , 3, stimulated by M2/M4 receptors occurred within approximately 2 min of agonist addition. The increases in Gq/11,-[35S]-GTP,S binding after M1 and M3 receptor stimulation differed substantially, with M1 receptors causing a 2 , 3 fold greater increase in [35S]-GTP,S binding and requiring 5 fold lower concentrations of methacholine to stimulate a half-maximal response. Comparison of M2 and M4 receptor-mediated Gi1 , 3,-[35S]-GTP,S binding also revealed differences, with M2 receptors causing a greater increase in Gi1 , 3, activation and requiring 10 fold lower concentrations of methacholine to stimulate a half-maximal response. Comparison of methacholine- and pilocarpine-mediated effects revealed that the latter partial agonist is more effective in activating Gi3, compared to Gi1/2, for both M2 and M4 receptors. More marked agonist/partial agonist differences were observed with respect to M1/M3 -mediated stimulations of Gq/11,- and Gi1 , 3,-[35S]-GTP,S binding. Whereas coupling to these G, subclasses decreased proportionately for M1 receptor stimulation by these agonists, pilocarpine possesses a greater intrinsic activity at M3 receptors for Gi, versus Gq/11, activation. These data demonstrate that mACh receptor subtype and the nature of the agonist used govern the repertoire of G proteins activated. They also provide insights into how the diversity of coupling can be pharmacologically exploited, and provide a basis for a better understanding of how multiple receptor subtypes can be differentially regulated. British Journal of Pharmacology (2001) 132, 950,958; doi:10.1038/sj.bjp.0703892 [source] Hippocampal long-term depression as an index of spatial working memoryEUROPEAN JOURNAL OF NEUROSCIENCE, Issue 5 2002Kazuhito Nakao Abstract Long-term potentiation (LTP), a form of synaptic plasticity in the hippocampus, is a cellular model for the neural basis of learning and memory, but few studies have investigated the contribution of long-term depression (LTD), a counterpart of LTP. To address the possible relationship between hippocampal LTD and spatial performance, the spatial cognitive ability of a rat was assessed in a spontaneous alternation test and, thereafter, LTD in response to low-frequency burst stimulation (LFBS) was monitored in the dentate gyrus of the same rat under anaesthesia. To enhance a divergence in the ability for spatial performance, some of the animals received fimbria,fornix (FF) transection 14 days before the experiments. LTD was reliably induced by application of LFBS to the medial perforant path of intact rats, while no apparent LTD was elicited in rats with FF lesions. The behavioural parameters of spatial memory showed a significant correlation with the magnitude of LTD. We found no evidence that the cognitive ability correlated with other electrophysiological parameters, e.g. basal synaptic responses, stimulus intensity to produce half-maximal responses, paired-pulse facilitation or paired-pulse depression. These results suggest that the magnitude of LTD in the dentate gyrus serves as a reliable index of spatial cognitive ability, providing insights into the functional significance of hippocampal LTD. [source] | |||||||||||||