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Query: UNIPROT:P06889 (Mol)
 630,302 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The dependence of electrogenic sodium pump activity on changes in the cell volume of Helix pomatia neurons with different levels of intracellular sodium ion concentration was studied. Hypertonic solutions caused hyperpolarization of the membrane and increased membrane resistance in cells with a low sodium content (low-sodium cells; LSC). The activity of the electrogenic sodium pump in hypertonic solutions was increased compared to the activity in hypotonic solutions in LSC and decreased in cells with a high sodium content (high-sodium cells; HSC). The concentration of ouabain which led to maximal inhibition of active 22Na efflux from the neurons was 10(-4) M. Lower concentrations of ouabain (10(-8) M and lower) did not inhibit the sodium pump but stimulated it. The swelling of neurons in hypotonic solutions was accompanied by an increase in the number of binding sites for ouabain, while shrinking in hypertonic solutions led to the opposite effect--a decrease in binding sites. An increase in the number of binding sites also took place in normal isotonic potassium-free solutions compared with normal Ringer's solution. Two saturable components of ouabain binding were detectable in all solutions examined. gamma-Aminobutyric acid (GABA) and acetylcholine (ACh) increased the number of ouabain binding sites on the membrane. The results suggest that there are two opposite mechanisms by which cell volume changes can modulate the pump activity. One of them depends on the intracellular sodium ion concentration and causes pump activation in hypertonic solutions in LSC and saturation in HSC, while a second mechanism mediates the activating effect of cell swelling on the sodium pump in HSC. In addition, there may be a negative feedback between the pump activity and the number of functioning pump units in the membrane.
Cell Mol Neurobiol 1984 Dec
PMID:Autoregulation of the electrogenic sodium pump. 624 43

This review describes a novel class of heterocyclic GABA uptake inhibitor with no affinity for the GABA receptors. The parent compound nipecotic acid is a potent inhibitor of neuronal and glial GABA uptake, and nipecotic acid is a substrate for the transport carriers concerned. The structurally related cyclic amino acids guvacine and cis-4-hydroxynipecotic acid are also potent inhibitors of both GABA transport systems. Even minor structural alterations of these compounds result in considerable or complete loss of activity. Whereas homonipecotic acid is a weak but selective inhibitor of glial GABA uptake, homoguvacine is virtually inactive. Similarly the lower homologues of nipecotic acid and guvacine, beta-proline and 3-pyrroline-3-carboxylic acid, respectively, show some selectivity with respect to inhibition of glial GABA uptake, but these compounds are much weaker than the parent compounds. The bicyclic compounds THPO and THAO, in which the carboxyl groups of nipecotic acid and homonipecotic acid have been replaced by 3-isoxazolol units are moderately potent and practically specific inhibitors of glial GABA uptake. cis-4-Mercaptonipecotic acid is considerably weaker than the closely related analogue cis-4-hydroxynipecotic acid, but the former compound may interact irreversibly with the GABA transport carriers. The results demonstrate a pronounced substrate specificity of the glial and in particular the neuronal GABA transport system. It is evident that the GABA molecule is transported in a conformation different from that, in which it activates its receptors. These findings are of importance for the development of drugs for selective pharmacological regulation of the functions of central GABA-mediated synapses in certain neurological diseases.
Mol Cell Biochem 1980 Jun 18
PMID:Inhibitors of the GABA uptake systems. 625 61

This review describes the development of GABA receptor agonists with no detectable affinity for other recognition sites in GABA-mediated synapses. The key compounds are THIP, isoguvacine, and piperidine-4-sulphonic acid (P4S), developed via extensive structural modifications of the potent but not strictly specific GABA agonist muscimol. The structural parameters, which have to be considered in the design of GABA agonists are discussed on the basis of the structures and biological activities of these GABA agonists and a number of related compounds. A model, which summarizes our present knowledge of the structure of the postsynaptic GABA receptors complex, is presented, and the interaction of GABA agonists with various sites in this complex is discussed. Of particular interest are the effects of GABA agonists on the binding of diazepam to the benzodiazepine binding site, assumed to be a structural unit of the GABA receptor complex. While rigid molecules like THIP are capable of activating the GABA receptors, a certain degree of conformational mobility of GABA agonists apparently is a prerequisite for stimulation of diazepam binding in vitro at 0 degree C. The findings suggest that GABA receptor functions involve conformational changes of certain elements, including the attempts to develop GABA agonists with desirable pharmacokinetic and toxicological characteristics. While muscimol is a toxic compound, THIP is well tolerated by animals, and in contrast to isoguvacine, THIP penetrates into the brain after systemic administration to animals, a difference which can be explained on the basis of their protolytic properties. The attempts to develop pro-drugs of isoguvacine capable of penetrating the blood-brain barrier with subsequent decomposition in the brain tissue to isoguvacine are described.
Mol Cell Biochem 1981 Aug 11
PMID:GABA agonists. Development and interactions with the GABA receptor complex. 627 May 44

In this paper it is shown that the postsynaptic GABA-receptor chloride ion channel complex is composed of several functional subunits. There are probably at least two stereospecific locations on the receptor for GABA-binding and both must be occupied to obtain an increase in chloride conductance. The interaction between these sites is uncertain but there could be either positive cooperativity between the sites or only a requirement that both sites are occupied without occupation of either site affecting the affinity for GABA of the other site. There is a chloride conductance channel coupled to the GABA receptor which opens for an average of 20 msec and has an average conductance of 18 pS. The GABA-coupled chloride channel may or may not have the same composition as the glycine coupled chloride channel. In addition to the GABA-recognition site and the chloride ion channel, GABA-receptors must have additional binding sites or modulator sites where drugs can bind to modify GABA activation of the GABA receptor. The convulsant PICRO binds to a site which is independent of the GABA site and PICRO reduces GABA responses. Barbiturates and benzodiazepines augment GABA-responses without reducing GABA-binding and thus they must bind to a modulator site independent of the GABA recognition site. Whether or not this is the same site as the PICRO binding site is uncertain. Thus, the GABA-receptor-chloride ion channel complex is composed of at least: 1) two GABA-binding sites; 2) a chloride ion channel; 3) a convulsant binding site (PICRO-binding site) and 4) an anticonvulsant binding site. This organization serves several obvious purposes. First, since two GABA-molecules are required to activate GABA-coupled chloride ion channels, the dose-response relationship for GABA is sigmoidal and steep. Thus minor shifts in GABA affinity will produce large alterations in GABA-responses and the GABA receptor can be easily modulated. Second, since the receptors has binding sites for convulsant and anticonvulsant compounds which decrease and increase GABA-responses, GABAergic inhibition can easily be modulated.
Mol Cell Biochem 1981 Aug 11
PMID:Pharmacology of GABA-mediated inhibition of spinal cord neurons in vivo and in primary dissociated cell culture. 627 May 45

The protein S100 markedly increases the net intake of GABA across the plasma membrane of Deiters' neurons which have GABA receptors on their surfaces. This membrane function of S100 was found by using a new microtechnique. Plasma membranes of such cells have been freshly prepared by freehand microsurgery and are tightly fixed over a 30-micrometers phi hole between two compartments of a microchamber containing 2.0 mM GABA in 7.5 microliters and 0.2 mM GABA in 75 microliters, respectively. The transport of GABA has been determined after incubation of the membrane for from 30 sec to 10 min at 29 degrees C. GABA is transported at a rate of 145 ng in 3 min over a 700-micrometers2 membrane area. S100 in its calcium form reacts with the membrane and increases GABA transport by 20% which is ATP dependent and inhibited by ouabain and ruthenium red. The kinetics of the transport furthermore prove that GABA transport across the plasma membrane is an active process.
Cell Mol Neurobiol 1981 Sep
PMID:The effect of S100 protein on the plasma membrane function of neurons. 628 28

The binding of [3H]Ro 5-4864 to the peripheral-type benzodiazepine binding site in brain is characterized. The binding is saturable, high-affinity (KD = 1.6 nM), and reversible. The comparison of [3H]Ro 5-4864 and [3H]diazepam binding sites reveals major differences which include the following. There are about one-fourth as many peripheral-type binding sites than central sites in brain. Peripheral sites are present in many extranervous tissues and have a brain regional distribution distinct from that of the central-type receptor. The [3H]Ro 5-4864 binding site also is apparently highly localized in the nuclear membrane in contrast to the central-type receptor, which is synaptosomal. gamma-Aminobutyric acid has no effect on [3H]Ro 5-8464 binding, again in contrast to its marked effect on [3H]diazepam binding. Various putative benzodiazepine receptor ligands, such as purines, beta-carbolines, and kynurenamines, are also inactive as inhibitors of [3H]Ro 5-4864 binding. Blocking the benzodiazepine receptor by photoaffinity labeling decreases [3H]diazepam binding by more than 80% and has no effect on [3H]Ro 5-4864 binding. These results indicate that the peripheral-type benzodiazepine binding site in brain is a separate entity whose physiological function is probably distinct from that of the central-type benzodiazepine receptor.
Mol Pharmacol 1982 Jul
PMID:Characterization of peripheral-type benzodiazepine binding sites in brain using [3H]Ro 5-4864. 628 73

t- Butylbicyclophosphorothionate ( TBPS ), a derivative of potent GABA antagonistic cage convulsants, has recently been introduced ( Squires , R. F., J.E. Casida , M. Richardson, and E. Saederup (1983) Mol. Pharmacol. 13:326-336) as ligand for a GABA-A receptor-linked drug receptor. Using conventionally prepared washed membrane fractions from rat cerebral cortex, we have confirmed that in the presence of 200 mM NaBr [35S] TBPS binds to a high affinity population of binding sites (Kd 26 +/- 5 nM) and that muscimol inhibits [35S] TBPS binding (IC50 0.32 microM) allosterically. In 200 mM NaCl the apparent affinity of [35S] TBPS binding sites is lower (Kd 60 +/- 5 nM), and muscimol has biphasic effects with stimulation at low concentrations of muscimol (EC50 0.023 microM) followed by inhibition at high concentrations (IC50 0.72 microM). Both base line [35S] TBPS binding (in 200 mM NaCl) and muscimol inhibition of [35S] TBPS binding (in 200 mM NaBr) are bidirectionally modulated by the occupancy of benzodiazepine receptors with its ligands. Benzodiazepine receptor agonists, regardless of their structure, enhance and inverse benzodiazepine receptor agonists inhibit base line [35S] TBPS binding and muscimol inhibition of [35S] TBPS binding. Fourteen ligands for benzodiazepine receptors display a similar in vitro profile as benzodiazepine receptor agonists or inverse benzodiazepine receptor agonists on [35S] TBPS binding as their anti- or proconvulsive effects in vivo suggest (Jensen, L. H., E. N. Petersen, and C. Braestrup (1983) Life Sci. 33: 393-399). That [35S] TBPS binding sites are constituents of a GABA benzodiazepine receptor complex is also suggested by a number of membrane pretreatments.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:[35S]-t-butylbicyclophosphorothionate binding sites are constituents of the gamma-aminobutyric acid benzodiazepine receptor complex. 632 34

Dissociated neonatal rat cerebellar cells were grown on medium supplemented with 10% horse serum (HS) and compared with those grown using a serum-free supplemented (SFS) medium, modified from Bottenstein and Sato (1979), containing insulin, transferrin, progesterone, putrescine, and selenium (after an initial 24 hr in 10% horse serum). Cells survived for several weeks using either medium. Cells grown in SFS had higher levels of GABA uptake than cells grown in HS. Cellular morphology and the proportion of neurons to glial cells were similar under the two conditions. Transferrin concentrations of 0.5, 10, and 100 micrograms/ml were tested. Neither neuronal nor glial cells were sensitive to this 200-fold variation. The SFS medium supports survival and maturation of both neurons and glial cells from rat cerebellum. However, the medium is not completely defined since (1) one day of serum is still required and (2) the heterogeneous cell population is undoubtedly conditioning the medium to some extent.
Cell Mol Neurobiol 1981 Mar
PMID:Growth of dissociated rat cerebellar cells using serum-free supplemented media and varied transferrin concentrations. 734 66

Phosphorylation of purified bovine brain GABAA receptors by the tyrosine kinase, pp60v-src was examined. pp60v-src phosphorylated two bands of 54-62 kDa and 48-51 kDa that migrated to approximately the same position as bands recognized by antisera against the beta 2 and gamma 2 GABAA receptor subunits, respectively. Bacterially expressed proteins containing the putative large cytoplasmic loops of the beta 1 and gamma 2L subunits were phosphorylated by pp60v-src, indicating that the phosphorylation sites are located in these subunit domains. The tyrosine kinase inhibitors, genistein and the tyrphostins B-42 and B-44, inhibited muscimol-stimulated 36Cl- uptake in mouse brain membrane vesicles (microsacs). magnitude of the tyrphostin B-44-induced inhibition of muscimol-stimulated 36Cl- uptake was significantly reduced in microsacs that were lysed and resealed under conditions that inhibit phosphorylation. GABA-gated Cl- currents were also inhibited by genistein and tyrphostin B-44 in Xenopus oocytes expressing alpha 1 beta 1 and alpha 1 beta 1 gamma 2L subunits. Consequently, protein tyrosine kinase-dependent phosphorylation appears to be another mechanism of regulating the function of GABAA receptors.
Brain Res Mol Brain Res 1995 Jul
PMID:Tyrosine kinase phosphorylation of GABAA receptors. 747 25

To investigate the molecular changes underlying kindling epileptogenesis in the rat hippocampus, the expression levels of the genes encoding for 13 different gamma-aminobutyric acid type-A receptor (GABAAR) subunits were measured in hippocampal principal neurons using in situ hybridization techniques and semi-quantitative analysis of the autoradiograms. Schaffer collateral-commissural pathway kindled rats were investigated at three different stages of kindling acquisition, at 24 h after the last seizure and at long-term (28 days) after termination of kindling stimulations. Changes were distinct for the different subunits in the three analyzed regions (CA1, CA3, fascia dentata) and also different for the various kindling stages. In all hippocampal areas at the early phases of kindling epileptogenesis, before the appearance of generalized seizures, an increase was found of those transcripts that constituted the majority of the expressed variants in control animals (alpha 1, alpha 2, alpha 4, beta 1, beta 2, beta 3, gamma 2/gamma 2L mRNA). In these stages, the increased levels of different variants in the granular neurons of the fascia dentata were more pronounced when compared to the pattern of changes in pyramidal cells of CA1 and CA3. In fully kindled animals, the expression levels of several subunits returned to control levels, whereas beta 3 and gamma 2/gamma 2L mRNA expression was still significantly enhanced in all areas. At long-term, few changes were encountered. The long-splice variant of gamma 2 was decreased within pyramidal and granular neurons while the total level of gamma 2 mRNA was not different from controls. The increased GABAAR subunit expression in the fascia dentata may underly the reported increased GABAAR ligand binding and the increased GABA mediated inhibition. However, the decreased GABAAR binding and the attenuation of GABAergic inhibition in CA1, could not be explained by a decrement of receptor subunit expression.
Brain Res Mol Brain Res 1995 Jul
PMID:Expression of GABAA receptor subunit mRNAs in hippocampal pyramidal and granular neurons in the kindling model of epileptogenesis: an in situ hybridization study. 747 32


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