Synaptosomal Transport: A Chloride Dependence for Choline, Gaba, Glycine and Several Other Compounds

Kuhar, Michael J.; Zarbin, Marco A.

doi:10.1111/j.1471-4159.1978.tb12456.x

Cited by 169 publications

(74 citation statements)

References 23 publications

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“…Iodide might have exerted an inhibitory effect on the uptake activity rather than acting as an inert anion, as observed in pantothenate uptake by Na ϩ -dependent multivitamin transporter (30). This 1 Cl Ϫ /1 choline coupling stoichiometry agrees with the result from high affinity choline uptake in brain synaptosomes, in which Cl Ϫ was replaced by acetate (31). Cl Ϫ -dependent uptake by WT and I89V were saturated in the investigated substitution range.…”

Section: Resultssupporting

confidence: 78%

Single Nucleotide Polymorphism of the Human High Affinity Choline Transporter Alters Transport Rate

Okuda

Okamura

Kaitsuka

et al. 2002

Journal of Biological Chemistry

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High affinity choline uptake plays a critical role in the regulation of acetylcholine synthesis in cholinergic neurons. Recently, we succeeded in molecular cloning of the high affinity choline transporter (CHT1), which is specifically expressed in cholinergic neurons. Here we demonstrate the presence of functionally relevant, nonsynonymous single nucleotide polymorphism in the human CHT1 gene by comprehensive sequence analysis of the exons and the intron/exon boundaries including the transcription start site. The deduced amino acid change for the polymorphism is isoleucine to valine at amino acid 89 (I89V) located within the third transmembrane domain of the protein. The allele frequency of I89V was 6% for Ashkenazi Jews. Functional assessment of the I89V transporter in mammalian cell lines revealed a 40 -50% decrease in V max for choline uptake rate compared with the wild type, whereas there was no alteration in the apparent affinities for choline, sodium, chloride, and the specific inhibitor hemicholinum-3. There also was no change in the specific hemicholinum-3 binding activity. The decreased choline uptake was not associated with the surface expression level of the protein as assessed by biotinylation assay. These results suggest an impaired substrate translocation in the I89V transporter. The Caenorhabditis elegans ortholog of CHT1 has a valine residue at the corresponding position and a single replacement from valine to isoleucine caused a decrease in the choline uptake rate by 40%, suggesting that this hydrophobic residue is generally critical in the choline transport rate in CHT1. This polymorphism in the allelic CHT1 gene may represent a predisposing factor for cholinergic dysfunction.

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Section: Resultssupporting

confidence: 78%

Single Nucleotide Polymorphism of the Human High Affinity Choline Transporter Alters Transport Rate

Okuda

Okamura

Kaitsuka

et al. 2002

Journal of Biological Chemistry

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“…(1) A number of membrane transport systems (Kanner, 1978;Kuhar & Zarbin, 1978;Ross, 1980;Nelson & Rudnick, 1982), including those for glutamate and aspartate in neural tissue (Kuhar & Zarbin, 1978;Marvizon et al, 1981;Waniewski & Martin, 1984), exhibit a Cl--requirement. Moreover, the anion specificity of these systems is similar to that for AP4-sensitive L-glutamate binding (Mena et al, 1982;Fagg et al, 1983a;Butcher et al, 1984), and corresponds generally to those anions known to permeate the plasma membrane.…”

Section: Discussionmentioning

confidence: 99%

Cl⁻/Ca²⁺‐dependent L‐glutamate binding sites do not correspond to 2‐amino‐4‐phosphonobutanoate‐sensitive excitatory amino acid receptors

Fagg¹,

Lanthorn²

1985

British J Pharmacology

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1 A series of phosphono and phosphino analogues of glutamate were used to compare the pharmacological properties of (a) ClP/Ca2+-dependent, 2-amino-4-phosphonobutanoate (AP4)-sen- (IC50 values> 1001iM). Inactive compounds which exhibited activity in the binding assay did not reverse the synaptic depressant effects of AP4, indicating that they were neither agonists nor antagonists at AP4-sensitive synapses. 4 The lack of correspondence between (a) the Cl-/Ca2 -dependent, AP4-sensitive population of L-[3H]-glutamate binding sites and (b) AP4-sensitive synaptic responses indicates that these binding sites are not the receptors through which AP4 exerts its neuropharmacological effects. The possibility that Cl-/Ca2+-dependent 'binding sites' represent transport into resealed SPM vesicles is discussed. 5 Electrophysiological data demonstrate that AP4-sensitive synaptic receptors display a high degree of ligand selectivity. High antagonist potency is shown only by glutamate analogues with unmodified a-amino and a-carboxyl groups, and with a bifunctional (dianionic) o-terminal.

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“…Specitic high-affinity transport systems have been identified in nerve terminals and glial cells for several amino acid neurotransmitters, including glycine (Johnston and Iversen, 197 1;Logan and Snyder, 1972;Kuhar and Zarbin, 1978;Zafra and Gimenez, 1986;Fedele and Foster, 1992). In the past few years, some of the neurotransmitter transporters have been purified from mammalian brain (Radian et al, 1986;Danbolt et al, 1990;Lopez-Corcuera et al, 1991) and, more recently, cDNA clones encoding transporters for GABA, catecholamines, serotonin, glycine, proline, and glutamate have been isolated (Guastella et al, 1990(Guastella et al, , 1992Blakely et al, 1991;Hoffman et al, 1991;Kilty et al, 1991;Pacholczyk et al, 1991;Shimana et al, 1991;Usdin et al, 199 1: Borden et al, 1992;Fremau et al, 1992;Giros et al, 1992;Kanai and Hediger, 1992;Pines et al, 1992;Liu et al, 1992Liu et al, , 1993Smith et al.…”

Section: Glycinementioning

confidence: 99%

Glycine transporters are differentially expressed among CNS cells

et al. 1995

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Glycine is the major inhibitory neurotransmitter in the spinal cord and brainstem and is also required for the activation of NMDA receptors. The extracellular concentration of this neuroactive amino acid is regulated by at least two glycine transporters (GLYT1 and GLYT2). To study the localization and properties of these proteins, sequence- specific antibodies against the cloned glycine transporters have been raised. Immunoblots show that the 50–70 kDa band corresponding to GLYT1 is expressed at the highest concentrations in the spinal cord, brainstem, diencephalon, and retina, and, in a lesser degree, to the olfactory bulb and brain hemispheres, whereas it is not detected in peripheral tissues. Pre-embedding light and electron microscopic immunocytochemistry show that GLYT1 is expressed in glial cells around both glycinergic and nonglycinergic neurons except in the retina, where it is expressed by amacrine neurons, but not by glia. The expression of a 90–110 kDa band corresponding to GLYT2 is restricted to the spinal cord, brain-stem, and cerebellum; in addition, very low levels occur in the diencephalon. GLYT2 is found in presynaptic elements of neurons thought to be glycinergic. However, in the cerebellum, GLYT2 is expressed both in terminal boutons and in glial elements. The physiological consequences of the regional and cellular distributions of these two proteins as well as the possibility of the existence of an unidentified neuronal form of GLYT1 are discussed.

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Synaptosomal Transport: A Chloride Dependence for Choline, Gaba, Glycine and Several Other Compounds

Cited by 169 publications

References 23 publications

Single Nucleotide Polymorphism of the Human High Affinity Choline Transporter Alters Transport Rate

Single Nucleotide Polymorphism of the Human High Affinity Choline Transporter Alters Transport Rate

Cl⁻/Ca²⁺‐dependent L‐glutamate binding sites do not correspond to 2‐amino‐4‐phosphonobutanoate‐sensitive excitatory amino acid receptors

Glycine transporters are differentially expressed among CNS cells

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Synaptosomal Transport: A Chloride Dependence for Choline, Gaba, Glycine and Several Other Compounds

Cited by 169 publications

References 23 publications

Single Nucleotide Polymorphism of the Human High Affinity Choline Transporter Alters Transport Rate

Single Nucleotide Polymorphism of the Human High Affinity Choline Transporter Alters Transport Rate

Cl−/Ca2+‐dependent L‐glutamate binding sites do not correspond to 2‐amino‐4‐phosphonobutanoate‐sensitive excitatory amino acid receptors

Glycine transporters are differentially expressed among CNS cells

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Cl⁻/Ca²⁺‐dependent L‐glutamate binding sites do not correspond to 2‐amino‐4‐phosphonobutanoate‐sensitive excitatory amino acid receptors