Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0004352 (autism)
 32,579 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Membrane vesicles, isolated after osmotic shock of synaptosomal rat brain fractions, actively accumulate L-glutamate. This process requires the presence of external sodium ions and internal potassium ions and is driven by artifically imposed ion gradients as the sole energy source. Either an Na+ gradient (out is greater than in) or a K+ gradient (in is greater than out) or both can be utilized to concentrate L-glutamate inside the vesicles. Transport is enhanced by valinomycin or by external thiocyanate ions and is about 50% inhibited by the proton ionophore carbonyl cyanide m-chlorophenylhydrazone. This transport thus appears to be stimulated by a membrane potential (interior negative). The glutamate transporter, the Km of which has been determined to be 3 micrometer, is specific for L-glutamate. The transport process is unaffected by ouabain but is strongly inhibited by p-hydroxymercuribenzoate as well as by nigericin, which collapses the energizing ion gradients across this membrane. Unlike the sodium dependent, but potassium independent active accumulation of gamma-aminobutyric acid in these vesicles (Kanner, B.I. (1978) Biochemistry 17, 1207) active L-glutamate uptake is not dependent on the presence of small monovalent anions in the external medium. The results provide direct evidence for Na+-coupled electrogenic active L-glutamate transport by rat brain membrane vesicles. The dependence on internal potassium ions is discussed.
 ...
PMID:Active transport of L-glutamate by membrane vesicles isolated from rat brain. 70 89

The reconstruction of the purified sodium- and chloride-coupled gamma-aminobutyric acid transporter from rat brain into asolectin liposomes requires the addition of brain lipids (Radian, R., and Kanner, B. I. (1985) J. Biol. Chem. 260, 11859-11865). The reconstitution assay was used to identify the component(s) from brain lipids responsible for the stimulation during the fractionation of brain lipids. The distribution of the active component was found to be similar to that of cholesterol. Furthermore, cholesterol was found to mimic the effect of brain lipids and it stimulated the transport activity up to 20-fold. Optimal reconstituted transport activity was achieved with mixtures of cholesterol and any one of several phospholipids, such as phosphatidylcholine, phosphatidylserine or phosphatidylglycerol. gamma-Aminobutyric acid transport in these liposomes of defined composition exhibited all the properties of the native transporter, such as the absolute dependence on sodium and chloride and electrogenicity. Cholesterol could not be replaced by cholest-4-en-3one and other steroids, and thus its effect is probably not due to effects on membrane fluidity. The requirement was also not due to effects on intactness of the liposomes or incorporation of proteins into them. Furthermore it was found that the reconstitution of the sodium and potassium coupled L-glutamic acid transporter from rat brain also required cholesterol. However, in this case the optimal activity was reached by 4-5-fold lower levels of cholesterol than those necessary for gamma-aminobutyric acid transport. When cholesterol depletion from the transporters was incomplete, addition of exogenous brain lipids was not required. Thus, if the cholesterol was still associated with the transporter proteins, its final concentration, as a fraction of the total lipids present in the reconstitution mixture, was only about 0.01 mol%. Thus, it is likely that the effects of cholesterol are due to direct interactions with the cotransporters and not to an average effect on membrane properties.
 ...
PMID:Cholesterol is required for the reconstruction of the sodium- and chloride-coupled, gamma-aminobutyric acid transporter from rat brain. 231 45

It is currently thought that aggregation of the receptor for immunoglobulin E on mast cells, basophils, and a tumor analog, rat basophilic leukemia (RBL) cells, induces an enhanced permeability of the plasma membrane to calcium, thereby initiating degranulation of the cells. Even in the absence of calcium ions, aggregation of the receptor causes depolarization of the plasma membrane (Kanner, B. I., and Metzger, H. (1983) Proc. Natl. Acad. Sci. U. S. A. 80, 5744-5748), suggesting that other ions can traverse the putative channel. Direct evidence for this now has been obtained with measurements of increased 22Na+ fluxes in the absence of calcium ions, induced by aggregation of receptors. This reaction was optimally studied in the presence of ouabain. When aggregation of the receptor was induced by reacting the cell-bound IgE with a multivalent antigen, the sodium flux was completely inhibited by univalent hapten. The sodium flux was also completely inhibited by 2 mM calcium. Aggregation-induced 45Ca2+ fluxes were observed in the presence of millimolar concentrations of external Ca2+, but not in its absence. Depolarization of the plasma membrane potential by the addition of potassium to the medium in the presence of calcium did not itself induce degranulation. In fact, aggregation of the receptors for IgE in the presence of high external potassium resulted in a greatly diminished degranulation. These data indicate that the ion channel modulated by aggregation of receptor differs from the voltage-dependent type of calcium channels. We suggest that in the absence of calcium this channel is rather unspecific, but that calcium can modify it to become calcium selective.
 ...
PMID:Initial characterization of the calcium channel activated by the cross-linking of the receptors for immunoglobulin E. 608 86

Synaptic plasma membrane vesicles isolated from rat brain were loaded with L-glutamate either passively, by using a freeze-thaw technique, or by active transport. Subsequently the ion dependency of glutamate efflux from these vesicles was studied. With each of the types of loading similar results were obtained. Efflux requires the simultaneous presence of internal sodium ions and external potassium ions. The process is also stimulated by chloride ions, but either internal or external chloride ions cause stimulation. Addition of unlabeled L-glutamate stimulates efflux about 2-fold. It is concluded that efflux of L-glutamate is in many aspects symmetrical with its influx [Kanner, B. I., & Sharon, I. (1978) Biochemistry 17, 3949--3954]. It appears that in order for L-glutamate to interact with the transporter, sodium has to be present on the same side as L-glutamate whereas potassium has to be simultaneously present on the opposite site. The simplest way to account for these and the previous data is to postulate that the L-glutamate transporter catalyzes sodium and L-glutamate cotransport, while it simultaneously catalyzes antiport of potassium.
 ...
PMID:Efflux of L-glutamate by synaptic plasma membrane vesicles isolated from rat brain. 612 9

The mechanism of gamma-aminobutyric acid translocation in synaptic plasma membrane vesicles from rat brain has been probed by comparing the ion dependency of net efflux with that of exchange. Furthermore the question has been asked if the same mechanism operates for other solutes translocated by this transporter. Dilution-induced efflux of gamma-aminobutyrate from the membrane vesicles is about 3-fold stimulated by externally added gamma-aminobutyrate. Half maximal stimulation is obtained at a gamma-aminobutyrate concentration similar to the Km for gamma-aminobutyrate influx. This stimulation (exchange) is dependent on external sodium but not on external chloride. In contrast to this gamma-aminobutyrate influx is absolutely dependent on the simultaneous presence of sodium and chloride ions (Kanner, B.I. (1978) Biochemistry 17, 1207-1211), while efflux is dependent on the presence of these two ions on the inside (Kanner, B.I. and Kifer, L. (1981) Biochemistry 20, 3354-3358). Nigericin stimulates dilution-induced efflux of gamma-aminobutyrate from potassium loaded vesicles to a larger extent than external gamma-aminobutyrate. gamma-Aminobutyrate further enhances the nigericin-induced stimulation, provided that the vesicles are not preloaded with chloride. Nipecotic acid is transported with the same features as gamma-aminobutyrate and the two solutes behave similar with respect to the ion dependence of net flux and exchange. A model for the translocation cycle is proposed in which at least one of the translocated sodium ions binds to the transporter in its 'outside' conformation after chloride and the solute have bound previously. Conversely, the solute is released from its 'inside' conformation prior to chloride and at least one of the sodium ions.
 ...
PMID:Efflux and exchange of gamma-aminobutyric acid and nipecotic acid catalysed by synaptic plasma membrane vesicles isolated from immature rat brain. 684 11

The excitatory neurotransmitter glutamate is removed from the synaptic cleft by several related sodium- and potassium-coupled transporters. They thereby restrict the neurotoxicity of this transmitter. Based on the accessibility of single cysteines to the large sulfhydryl reagent 3-N-maleimidyl(propionyl)biocytin, we have proposed a topological model for the astroglial glutamate transporter GLT-1 (Grunewald, M., Bendahan, A. and Kanner, B. I. (1998) Neuron 21, 623-632). Because of several unexpected observations, we have investigated the topological disposition of 19 cysteine residues engineered into a loop proposed to be intracellular. We have probed the accessibility of these cysteines to small and large sulfhydryl reagents. The impermeant hydrophilic sulfhydryl reagent [(2-trimethylammonium)ethyl] methanethiosulfonate inhibits transport activity only at two of these positions, weakly at G365C and potently at A364C. Glutamate and its nontransportable analogue dihydrokainate markedly protect A364C transporters against this impermeant reagent. Using a biotinylated maleimide, we found that, among the 14 mutants tested with it, only A364C is accessible to it from the extracellular side. This, together with our previous observations, indicates that the loop-including amino acid residues 354, 359, 373, and 379-is largely intracellular, but a short region of it forms a reentrant pore-loop-like structure, the accessibility of which is dependent on the conformation of the transporter.
 ...
PMID:The accessibility of a novel reentrant loop of the glutamate transporter GLT-1 is restricted by its substrate. 1073 20

The substrate-binding sites in membrane transporters are alternately accessible from either side of the membrane, but the molecular basis of how this alternate opening of internal and external gates is achieved is largely unknown. Here we present data indicating that, in the neuronal electrogenic sodium- and potassium-coupled glutamate transporter EAAC-1, the substrate-binding site and one of the gates, or a residue controlling the gating process, are in close physical proximity. Arginine 445, located only two residues away from a residue implicated in glutamate binding (Bendahan, A., Armon, A., Madani, N., Kavanaugh, M. P., and Kanner, B. I. (2000) J. Biol. Chem. 275, 37436-37442), has been mutated to serine (R445S). Upon expression in oocytes, measurements of l-[(3)H]-glutamate transport under voltage clamp reveal that the charge/flux ratio for l-glutamate at -60 mV is approximately 30-fold higher than that of the wild type. Also, with d-aspartate, R445S exhibits an approximately 15-fold increase in this ratio. In contrast to the wild type, the reversal potential of the substrate-dependent currents in R445S shifts to more negative potentials when either the external sodium or potassium concentration is decreased. These findings indicate that these two cations are the main current carriers in the R445S mutant. Introduction of a methionine or a glutamine, but not a lysine, at position 445 gives rise to a phenotype similar to R445S. Therefore, it seems that the elimination of a positive charge in the vicinity of the substrate-binding site converts the transporter into a glutamate-gated cation-conducting pathway.
 ...
PMID:Arginine 445 controls the coupling between glutamate and cations in the neuronal transporter EAAC-1. 1459 97

The recent suggestion that secretin may be useful in treating autism and schizophrenia has begun to focus attention on the mechanisms underlying this gut-brain peptide's actions in the central nervous system (CNS). In vitro autoradiographic localization of (125)I-secretin binding sites in rat brain shows the highest binding density in the nucleus tractus solitarius (NTS). Recent evidence suggests that intravenous infusion of secretin causes fos activation in NTS, a relay station playing important roles in the central regulation of autonomic functions. In this study, whole cell patch-clamp recordings were obtained from 127 NTS neurons in rat medullary slices. The mean resting membrane potential of these neurons was -54.7 +/- 0.3 mV, the mean input resistance was 3.7 +/- 0.2 GOmega, and the action potential amplitude of these neurons was always >70 mV. Current-clamp studies showed that bath application of secretin depolarized the majority (80.8%; 42/52) of NTS neurons tested, whereas the remaining cells were either unaffected (17.3%; 9/52) or hyperpolarized (1.9%; 1/52). These depolarizing effects were maintained in the presence of 5 microM TTX and found to be concentration dependent from 10(-12) to 10(-7) M. Using voltage-clamp techniques, we also identified modulatory actions of secretin on specific ion channels. Our results demonstrate that while secretin is without effect on net whole cell potassium currents, it activates a nonselective cationic conductance (NSCC). These results show that NTS neurons are activated by secretin as a consequence of activation of a NSCC and support the emerging view that secretin can act as a neuropeptide within the CNS.
 ...
PMID:Secretin depolarizes nucleus tractus solitarius neurons through activation of a nonselective cationic conductance. 1471 95

Scores of monogenic Mendelian ion channel diseases serve to anchor the pathophysiology of the channelopathies, but there are also now clear examples of environmental, pharmacogenetic, and acquired channelopathy mechanisms. The cardinal feature of heritable ion channel disease is a periodic disturbance of rhythmic function in constitutionally hyperexcitable tissue. While the complexity of neuroanatomy obscures functional analysis of mutations causing monogenic seizure, ataxia, or migraine syndromes, extrapolation from the cardiac (Long QT [LQT]) and muscle (Periodic Paralysis) channelopathy syndromes provides a simplified predictive framework of molecular pathology: electrically stabilizing potassium ion (K(+)) and chloride ion (Cl(-)) channels, likely having lesions that diminish their current, and excitatory Na(+) channels, likely having gain-of-function lesions. The voltage-gated calcium channel gene family that contains CACNA1C, the newest LQT locus, causing Timothy Syndrome with a phenotype including autism, has proven to be particularly informative for its members' ability to tie the various central nervous system (CNS) phenotypes together in an interpretable fashion, now including direct extension to the classically multigenic neuropsychiatric phenotypes. Features of a promising ion channel candidate gene arise from its broad locus, gene family, nature of alleles, physiology and pharmacology, tissue expression profile, and phenotype in model organisms. KCNN3 is explored as a paradigm to consider.
 ...
PMID:Ion channel functional candidate genes in multigenic neuropsychiatric disease. 1649 76

The objective of this study was to assess the levels of 39 toxic metals and essential minerals in hair samples of children with autism spectrum disorders and their mothers compared to controls. Inductively coupled plasma-mass spectrometry was used to analyze the elemental content of the hair of children with autism spectrum disorders (n=51), a subset of their mothers (n=29), neurotypical children (n=40), and a subset of their mothers (n=25). All participants were recruited from Arizona. Iodine levels were 45% lower in the children with autism (p=0.005). Autistic children with pica had a 38% lower level of chromium (p=0.002). Autistic children with low muscle tone had very low levels of potassium (-66%, p=0.01) and high zinc (31%, p=0.01). The mothers of young children with autism had especially low levels of lithium (56% lower, p=0.005), and the young children (ages 3-6 yr) with autism also had low lithium (-30%, p=0.04). Low iodine levels are consistent with previous reports of abnormal thyroid function, which likely affected development of speech and cognitive skills. Low lithium in the mothers likely caused low levels of lithium in the young children, which could have affected their neurological and immunological development. Further investigations of iodine, lithium, and other elements are warranted.
 ...
PMID:Analyses of toxic metals and essential minerals in the hair of Arizona children with autism and associated conditions, and their mothers. 1684 57


1 2 3 4 5 6 Next >>