Acetylcholine active transport by rat brain synaptic vesicles

Haigh, Julian R.; Noremberg, Krystyna; Parsons, Stanley M.

doi:10.1097/00001756-199403000-00009

Cited by 17 publications

(16 citation statements)

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“…In order to confirm that the transport activity of this mutant is dependent on the H ϩ -ATPase, we determined the dependence of the transport assay on Mg-ATP, as well as the effect of the proton ionophore FCCP, or in the specific V type ATPase inhibitor bafilomycin A1 (31,32). Since the V-type ATPase is sensitive to low temperature (33,34), we also examined transport activity at 0°C. As shown in Fig.…”

Section: Mutation Of Aspartate Residues In the Cytoplasmic Loops-mentioning

confidence: 99%

Mutational Analysis of Aspartate Residues in the Transmembrane Regions and Cytoplasmic Loops of Rat Vesicular Acetylcholine Transporter

Kim

Lim

et al. 1999

Journal of Biological Chemistry

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The vesicular acetylcholine transporter (VAChT) is responsible for the transport of the neurotransmitter acetylcholine (ACh) into synaptic vesicles using an electrochemical gradient to drive transport. Rat VAChT has a number of aspartate residues within its predicted transmembrane domains (TM) and cytoplasmic loops, which may play important structural or functional roles in acetylcholine transport. In order to identify functional charged residues, site-directed mutagenesis of rVAChT was undertaken. No effect on ACh transport was observed when any of the five aspartate residues in the cytoplasmic loop were converted to asparagine. Similarly, changing Asp-46 (D46N) in TM1 or Asp-255 (D255N) in TM6 had no effect on ACh transport or vesamicol binding.

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Section: Mutation Of Aspartate Residues In the Cytoplasmic Loops-mentioning

confidence: 99%

Mutational Analysis of Aspartate Residues in the Transmembrane Regions and Cytoplasmic Loops of Rat Vesicular Acetylcholine Transporter

Kim

Lim

et al. 1999

Journal of Biological Chemistry

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“…2. Correction and refinement of micol inhibition of --'200 nM and Km and Vmax values this model will be based on the assumption of similar for ACh uptake of 5 mM and 4 nmol/min/mg of promechanisms of transport for both VMATs and tein, respectively (Haigh et al, 1994). ACh uptake YAChT, and acquisition of more structure/function into crude membrane or vesicle preparations from data for each.…”

Section: Vacht Transporter Function: 1993) It Interferes With Ach Stmentioning

confidence: 99%

The Cholinergic Gene Locus

Eiden

1998

Journal of Neurochemistry

185

121

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Messenger RNAs and the cognate gene(s) entions require the protein machinery for ACh synthesis coding choline acetyltransferase (ChAT) and the vesicuand sequestration to be expressed in particular neurons lar acetyicholine transporter (VAChT) have been cloned at particular locations, including motor neurons, parafrom mammals and several other animal classes in the sympathetic autonomic neurons, brainstem reticular last decade. These have provided molecular tools for inactivating neurons, and basal forebrain projection nellvestigating acetylcholine synthesis and packaging into rons. synaptic vesicles, the genesis of cholinergic vesicles, andThe neurotransmitter properties of ACh were disthe development and senescence of the cholinergic nervous system. VAChT and ChAT have been found to share covered by Loewi (1921

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“…Identification of benzovesamicol ( 2 , BVM, Figure 1 ) was a significant achievement, as this structural modification not only retained the high VAChT affinity, but also offered position(s) on the aromatic ring in the tetralin fragment for introducing substitution group(s). [19-22] Among the benzovesamicol analogues shown in Figure 1 , 5-( N -methyl-amino)benzovesamicol ( 3 , MABV) and N -ethyl-fluoroacetamidobenzovesamicol ( 4 , NEFA) are more potent inhibitors and more selective for VAChT versus σ receptors than vesamicol. [23] Furthermore, the single-photon emission computerized tomography (SPECT) radiotracer (-)-5-[ 123 I]iodo-benzovesamicol ([ 123 I] 5 , [ 123 I]IBVM) was used for mapping cholinergic terminals in the human brain [7-9, 24-27] although quantification of peak uptake in the target regions required at least 6 hr post-injection (p.i.).…”

Section: Introductionmentioning

confidence: 99%

Synthesis and biological characterization of a promising F-18 PET tracer for vesicular acetylcholine transporter

Zhang

Jin

et al. 2015

Bioorganic & Medicinal Chemistry

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Nine fluorine-containing vesicular acetylcholine transporter (VAChT) inhibitors were synthesized and screened as potential PET tracers for imaging the VAChT. Compound 18a was one of the most promising carbonyl-containing benzovesamicol analogues; the minus enantiomer, (-)-18a displayed high potency (VAChT Ki = 0.59 ± 0.06 nM) and high selectivity for VAChT versus receptors (> 10,000-fold). The radiosynthesis of (-)-[18F]18a was accomplished by a two-step procedure with 30 – 40% radiochemical yield. Preliminary biodistribution studies of (-)-[18F]18a in adult male Sprague–Dawley rats at 5, 30, 60 and 120 min post-injection (p.i.) were promising. The total brain uptake of (-)-[18F]18a was 0.684 ID%/g at 5 min p.i. and by 120 min p.i. slowly washed out to 0.409 %ID/g.; evaluation of regional brain uptake showed stable levels of ~0.800 %ID/g from 5 to 120 min p.i in the VAChT-enriched striatal tissue of rats, indicating the tracer had crossed the blood brain barrier and was retained in the striatum. Subsequent microPET brain imaging studies of (-)-[18F]18a in nonhuman primates (NHPs) showed high striatal accumulation in the NHP brain; the standardized uptake value (SUV) for striatum reached a maximum value of 5.1 at 15 min p.i. The time-activity curve for the target striatal region displayed a slow and gradual decreasing trend 15 min after injection, while clearance of the radioactivity from the cerebellar reference region was much more rapid. Pretreatment of NHPs with 0.25 mg/kg of the VAChT inhibitor (-)-vesamicol resulted in a ~90% decrease of striatal uptake compared to baseline studies. HPLC metabolite analysis of NHP plasma revealed that (-)-[18F]18a had a good in vivo stability. Together, these preliminary results suggest (-)-[18F]18a is a promising PET tracer candidate for imaging VAChT in the brain of living subjects.

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Acetylcholine active transport by rat brain synaptic vesicles

Cited by 17 publications

References 0 publications

Mutational Analysis of Aspartate Residues in the Transmembrane Regions and Cytoplasmic Loops of Rat Vesicular Acetylcholine Transporter

Mutational Analysis of Aspartate Residues in the Transmembrane Regions and Cytoplasmic Loops of Rat Vesicular Acetylcholine Transporter

The Cholinergic Gene Locus

Synthesis and biological characterization of a promising F-18 PET tracer for vesicular acetylcholine transporter

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