Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:2.7.11.8 (FAST)
758 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The FAST and SLOW lines of mice are being selectively bred in replicate for differential sensitivities to the locomotor activating effects of ethanol. Whereas FAST-1 and FAST-2 mice are stimulated by 2.0 g/kg ethanol, SLOW-1 and SLOW-2 mice are not stimulated, and are often depressed, by this dose. The dopamine antagonists, SCH-23390 (D1) and raclopride (D2), produced dose-dependent decreases in the locomotor activity of EtOH-naive mice of both lines and replicates; however, FAST and SLOW mice were not differentially sensitive to these effects. The absence of a line difference in activity response to the dopamine antagonists suggests that dopamine receptor function has not been altered by selective breeding for differences in sensitivity to the stimulant effects of ethanol. The ethanol-stimulated activity of FAST-1 and FAST-2 mice was decreased by administration of the dopamine antagonists, haloperidol and raclopride, at doses that had no effect on basal locomotor activity. SCH-23390 decreased ethanol-stimulated activity of FAST-1, but not FAST-2 mice. The ethanol-induced activity changes of SLOW mice were generally unaffected by antagonist administration. These results suggest a role for dopaminergic systems in mediating ethanol-stimulated activity in selectively bred FAST mice. Coadministration of SCH-23390 and raclopride decreased ethanol-induced activation to a greater degree than either drug alone, further suggesting that both D1 and D2 receptor systems contribute to the full expression of the ethanol stimulant response.
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PMID:Dopamine antagonist effects on locomotor activity in naive and ethanol-treated FAST and SLOW selected lines of mice. 759 19

Increased recognition of the advantages of genetic animal models has led to heightened interest in their use and development. A replicated bidirectional selective breeding project has produced lines of mice that differ in their locomotor responses to 2.0 g/kg ethanol. FAST-1 and FAST-2 mice are highly stimulated by ethanol (EtOH), whereas SLOW-1 and SLOW-2 mice are either not affected or respond with locomotor depression. Current heritability estimates indicate that approximately 6-8% of the response variance in the FAST lines and 2-10% of the response variance in the SLOW lines is of additive genetic origin. Little systematic response to selection has occurred in recent generations, which implies that the limits of selection have been reached. Analysis of saline activity over 35 generations of selection indicates that baseline activities have not changed during the course of selection in three of the lines, whereas baseline activity of FAST-1 mice has increased slightly. In EtOH dose-response studies (0.5-3.0 g/kg), FAST mice had biphasic dose-response curves, whereas the locomotor activity of SLOW mice was either unaffected or depressed by all doses of EtOH. In addition, FAST mice spent more time in motion, traveled farther per movement, traversed greater distances in the center of the test chamber, and ambulated more quickly than SLOW mice when given EtOH. FAST and SLOW mice differed in EtOH clearance rates; however, the differences were slight relative to the large difference in locomotor response. We encourage the use of FAST and SLOW mice to investigate neurophysiological factors underlying sensitivity to the behavioral effects of EtOH, with a view to further testing of the postulated homology between locomotor stimulant effects and addiction potential of drugs of abuse.
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PMID:Bidirectional selective breeding for ethanol effects on locomotor activity: characterization of FAST and SLOW mice through selection generation 35. 856 Dec 96

We have investigated mesoderm induction in zebrafish employing the zebrafish LTR-retroelement bhikhari (bik). bik elements are transcribed in all early mesendodermal cells. This expression pattern is generated by a promoter located in the U3 region of the LTR. We show that bik is activated through the activin/Vg1 signaling pathway in an immediate early fashion. This activation critically depends on a sequence motif that occurs among others also in the Xenopus Mix2 activin response element (ARE). It has been shown that the Mix2 ARE binds FAST- 1, which complexes with Smad proteins to form a multi-protein complex. We confirm that also the bik ARE can be bound by FAST-1 in vitro. In animal cap experiments we demonstrate that this binding site is required for activin-induced transcriptional activation mediated by FAST and Smad-type proteins.
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PMID:Promoter activity of the zebrafish bhikhari retroelement requires an intact activin signaling pathway. 1041 54

We have examined the role of the maternally encoded transcription factor FAST-1 in the establishment of the mesodermal transcriptional program in Xenopus embryos. FAST-1 has been shown to associate with Smad2 and Smad4, transducers of TGFbeta superfamily signals, in response to stimulation by several TGFbeta superfamily ligands. The FAST-1/Smad2/Smad4 complex binds and activates a 50 bp activin responsive element identified in the promoter of the meso-endodermal marker Mix.2. We have now used three complementary approaches to demonstrate that FAST-1 is a central regulator of mesoderm induction by ectopic TGFbeta superfamily ligands and during endogenous patterning: ectopic expression of mutationally activated FAST-1, ectopic expression of dominant inhibitory FAST-1, and injection of a blocking antibody specific for FAST-1. Expression of constitutively transcriptionally active FAST-1 fusion protein (FAST-VP16(A)) in prospective ectoderm can directly induce the same set of general and dorsal mesodermal genes, as well as some endodermal genes, as are induced by activin or Vg1. In intact embryos, this construct can induce secondary axes similar to those induced by activin or Vg1. Conversely, expression of a FAST-1-repressor fusion (FAST-En(R)) in prospective ectoderm blocks induction of mesodermal genes by activin, while expression of FAST-En(R) in intact embryos prevents general/dorsal mesodermal gene expression and axial development. Injection of a blocking antibody specific for FAST-1 prevents induction of mesodermal response genes by activin or Vg1, but not by FGF. In intact embryos, this antibody can prevent the expression of early mesodermal markers and inhibit axis formation, demonstrating that FAST-1 is a necessary component of the first steps in the specification of mesoderm.
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PMID:FAST-1 is a key maternal effector of mesoderm inducers in the early Xenopus embryo. 1057 39

Earlier studies using the grid test have indicated a negative genetic correlation between sensitivity to ethanol-induced locomotor stimulation and ethanol-induced motor incoordination in FAST and SLOW mice, lines selectively bred for differential sensitivity to ethanol's stimulant effects. Because different tests of motor coordination may not measure the same behavioral competencies or physiological substrates, the present experiments tested adult ethanol- or saline-exposed FAST and SLOW mice of two replicates (FAST-1, FAST-2, SLOW-1, and SLOW-2) using three additional tests of coordination: a stationary dowel, fixed-speed rotarod, and accelerating rotarod. After ethanol treatment, FAST-1 mice fell from the stationary dowel at shorter latencies than SLOW-1 mice, suggesting that they had relatively greater sensitivity to ethanol. However, brain ethanol concentrations (BrECs) were similar at time of fall, and no differences were found between replicate-2 lines. SLOW-1 mice fell from the fixed-speed rotarod at lower BrECs than FAST-1 mice, suggesting possibly greater sensitivity of the SLOW-1 line. Again, no replicate-2 line differences were found. No significant differences were detected for the accelerating rotarod. These results provide little support for a negative genetic relationship between sensitivity to the stimulant and ataxic effects of ethanol using these measures of motor coordination.
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PMID:Sensitivity to ethanol-induced motor incoordination in FAST and SLOW selectively bred mice. 1088 Jun 75

FAST and Runx (CBFa) transcription factors, which are expressed during specific phases of embryogenesis and tissue patterning, bind directly to Smad proteins and integrate effects induced by various TGF-beta gene family members. The DNA binding sequences for FAST and Runx differ only minimally. The isoform Runx2 (previously termed CBFa1) is highly expressed by osteoblasts and regulates expression of the TGF-beta receptor I in these cells. Here we show that FAST-dependent transcription is endogenously restricted in osteoblasts but can be significantly enhanced by disruption of Runx2 expression. Native and synthetic Runx2 bind to both Runx and FAST binding sequences, whereas FAST-1 efficiently binds only to the FAST binding sequence. However, overexpression of FAST-1 potently suppresses TGF-beta receptor I gene expression in osteoblasts and thereby reduces TGF-beta activity independently of competing for Runx2 at the level of DNA binding. These results provide a new example of how nuclear factors associated with specific developmental states or tissue lineages may influence TGF-beta-dependent events in restricted ways.
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PMID:Control and counter-control of TGF-beta activity through FAST and Runx (CBFa) transcriptional elements in osteoblasts. 1151 65

Mice selectively bred for divergent sensitivity to the locomotor stimulant effects of ethanol (FAST and SLOW) also differ in their locomotor response to morphine. The GABA(B) receptor has been implicated in the mediation of locomotor stimulation to both ethanol and morphine, and a reduction in ethanol-induced stimulation has been found with the GABA(B) receptor agonist baclofen in FAST mice. We hypothesized that GABA(B) receptor activation would also attenuate the locomotor stimulant responses to morphine in these mice. In order to test this hypothesis, baclofen was administered to FAST-1 and FAST-2 mice 15 min prior to morphine, and activity was recorded for 30 min. Baclofen attenuated stimulation to 32 mg/kg morphine in FAST-1 mice, but only at a dose that also reduced saline activity. There was no stimulant response to 32 mg/kg morphine in FAST-2 mice, or to 16 mg/kg or 48 mg/kg morphine in FAST-1 mice, but the combination of baclofen with these morphine doses accentuated locomotor activity. Therefore, it appears that GABA(B) receptor activation is not a common mechanism for the locomotor stimulant responses to ethanol and morphine in FAST mice; however, these data suggest that GABA(B) receptor activation may instead enhance some of the behavioral effects of morphine.
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PMID:GABAB receptor stimulation accentuates the locomotor effects of morphine in mice bred for extreme sensitivity to the stimulant effects of ethanol. 1716 60

Icatibant is a selective antagonist of the bradykinin type 2 receptor. In the randomized, double-blind, multicentre, FAST-1 trial, the difference in the median time to the onset of symptom relief (primary endpoint) did not reach statistical significance between a single dose of subcutaneous icatibant 30 mg and placebo in adults with moderate to very severe acute abdominal or cutaneous episodes of hereditary angioedema. However, icatibant was effective with regard to several other endpoints, providing significantly greater reductions from baseline in symptom severity scores 4 and 12 hours after administration, and eliciting significantly shorter times to both first symptom improvement and overall patient improvement than placebo. In the similarly designed, active comparator-controlled, FAST-2 trial, a single dose of subcutaneous icatibant 30 mg was associated with a significantly shorter median time to onset of symptom relief (primary endpoint) than oral tranexamic acid in adults with acute abdominal or cutaneous episodes of hereditary angioedema, and was also more effective than tranexamic acid in terms of most other endpoints. Across both FAST-1 and -2, the efficacy of subcutaneous icatibant 30 mg in the treatment of laryngeal episodes of hereditary angioedema was generally consistent with that seen for abdominal and cutaneous episodes, with a median time to first symptom improvement of 0.6-1.0 hours. Subcutaneous icatibant was generally well tolerated in adult patients with hereditary angioedema in the FAST trials, with the most common adverse events being injection-site reactions that were generally of mild severity, transient in nature and resolved spontaneously without treatment.
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PMID:Icatibant. 2003 Apr 26

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