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Query: UNIPROT:P06889 (Mol)
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Various alpha and beta 3 subunit-specific antibodies were used to characterize some of the heterogeneous ligand-binding properties of gamma-aminobutyric acidA receptors. Polyclonal antibodies that were raised against the cytoplasmic amino acid sequence (380-392) of the rat beta 3 subunit recognized a single polypeptide of molecular mass of 58 kDa in Western blots with Ro7-1986 affinity-purified GABAA receptors from the rat brain, and a doublet of molecular mass of 54 kDa and 56 kDa in receptors from the bovine cortex, hippocampus, and cerebellum. Deglycosylation of purified receptors from the bovine cortex with N-glycanase resulted in a single band immunostained at molecular mass of 52 kDa. These anti-beta 3 subunit antibodies immunoprecipitated approximately 50% of [3H]flunitrazepam binding sites from soluble extracts of bovine cortex, whereas beta cyto antibodies, which probably recognize all beta subunit isoforms, precipitated almost 100% of benzodiazepine binding sites. These results indicate heterogeneity of GABAA receptor subunit composition with respect to the nature of beta subunits. The GABA analogue 4,5,6,7-tetrahydroisoxazolo[5,4-c]pyridin-3-ol (THIP), like GABA, shows heterogeneous binding affinities in brain homogenates. The higher affinity sites were previously suggested as corresponding to a 58-kDa polypeptide in rat that is photoaffinity-labeled with [3H]muscimol, a band that comigrates with the one stained by anti-beta 3 antibodies. However, THIP affinity was not significantly different between receptors containing beta 3 subunits and those lacking beta 3, as demonstrated by similar affinities in receptors that ere immunoprecipitated by anti-beta 3 antibodies and those that were not. Also, THIP displaced [3H]muscimol binding with similar multiple affinities across brain regions where different beta subunit variants are expressed with varying abundances. These observations suggest that the property of high affinity THIP binding cannot be explained solely by beta 3 subunits. The coupling efficiency between GABA and benzodiazepine binding sites appears to be determined by the nature of alpha subunits rather than of beta subunits. GABA enhanced [3H]flunitrazepam binding with different efficacies and potencies in receptors immunoprecipitated by anti-alpha 1, -alpha 2, and -alpha 3 subunit antibodies. In contrast, beta 3 subunit-enriched and disenriched receptors did not differ in this property. [3H]Flunitrazepam binding in GABAA receptors containing alpha 2 and alpha 3 subunits was enhanced to a significantly greater extent than were those with alpha 1. In addition, receptors containing alpha 1 and alpha 3 subunits had higher potencies of enhancement than did those with alpha 2 subunits.(ABSTRACT TRUNCATED AT 400 WORDS)
Mol Pharmacol 1995 Oct
PMID:Pharmacological subtypes of the gamma-aminobutyric acidA receptors defined by a gamma-aminobutyric acid analogue 4,5,6,7-tetrahydroisoxazolo[5,4-c] pyridin-3-ol and allosteric coupling: characterization using subunit-specific antibodies. 747 92

The influence of the monovalent cations (Na+ and K+) and of the electrical gradient on the high-affinity [3H]-gamma-aminobutyric acid ([3H]GABA) transport was investigated in synaptic plasma membrane (SPM) vesicles isolated from sheep brain cortex. This process specifically requires internal K+, since when it is replaced by Li+, the delta psi remains of the same order of magnitude, but no uptake of [3H]GABA occurs. The influence of the external Na+ concentration on the rate of [3H]GABA uptake suggests that this mechanism exhibits two components, whose characteristics are determined by the delta psi. Depolarization reduces the Jmax of [3H]GABA influx and enhances the binding of Na+ associated to [3H]GABA transport. Nevertheless, depolarization does not affect the K0.5 of binding sites for Na+ and the stoichiometry of translocation. These results suggest that intravesicular K+ and external Na+ have a dual role on the mechanism of [3H]GABA uptake: K+ acts directly on the carrier and determines the membrane polarization; Na+ is cotransported with GABA and, according to the polarization state of the membrane, it modulates the operation of the carrier in its inward GABA translocation.
Brain Res Mol Brain Res 1995 Aug
PMID:Dual role of K+ and Na+ on the transport of [3H]-gamma-aminobutyric acid by synaptic plasma membrane vesicles. 749 56

The ability of ovarian steroids to regulate the excitability of hippocampal neurons may be mediated by alterations in the inhibitory activity of GABA. We assessed the ability of estradiol, progesterone, and 3 alpha-OH-5 alpha-pregnan-20-one (3 alpha-OH-DHP; a metabolite of progesterone) to regulate gene expression of selected GABAA receptor subunits (alpha 1, alpha 2, beta 1, beta 2, and gamma 2). Using in situ hybridization, we found that progesterone, or 3 alpha-OH-DHP, suppressed mRNA levels for the alpha 1 subunit in the CA2, CA3, and the dentate gyrus subfields of the hippocampus in animals that were pretreated with estradiol. Progesterone had a more limited effect on the alpha 2 subunit, suppressing mRNA levels in estradiol-primed animals only in the CA3 region. In contrast, progesterone increased mRNA levels for the gamma 2 subunit in the CA1, CA2, and CA3 regions of the hippocampus, but only in animals that were not estradiol-primed. Estradiol alone had no significant effect on the expression of any subunit examined. Beta 1 and beta 2 subunit mRNA levels were not altered by any of the hormones tested. These data support the conclusion that progesterone and its metabolites may regulate excitability of the hippocampus by modulating the GABAA receptor gene expression; these effects of progesterone are dependent upon the circulating levels of estradiol. Alterations in the gene expression of selective subunits may lead to changes in the density of GABAA receptor protein or to changes in receptor subunit composition which might alter receptor sensitivity to activation by GABA or modulators such as the benzodiazepines and convulsants.
Brain Res Mol Brain Res 1995 Sep
PMID:Specific subunit mRNAs of the GABAA receptor are regulated by progesterone in subfields of the hippocampus. 750 Aug 38

The mRNA levels encoding neuropeptides were measured in the caudate nucleus, putamen and nucleus accumbens of common marmosets exposed to 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine pyridine (MPTP). Motor deficits induced by MPTP treatment were characterized by akinesia, postural abnormalities and rigidity. Seven days after MPTP treatment, there was a marked increase in levels of enkephalin mRNA in the caudate nucleus and putamen. In contrast, the hybridization signal for substance P mRNA was reduced. Alterations in the mRNA encoding neuropeptides were similar but less extensive in marmosets at 18-50 months following MPTP treatment. No significant changes in enkephalin or substance P mRNA in the nucleus accumbens were observed at either time. Treatment with L-DOPA plus carbidopa for 4 weeks reversed MPTP-induce motor deficits and other behavioural abnormalities. The decrease in substance P mRNA in the striatum of MPTP-treated animals was reversed by L-DOPA treatment and reached levels above those found in normal animals. In contrast, the increase in enkephalin mRNA in marmosets treated with MPTP was not altered by L-DOPA treatment. In the nucleus accumbens the levels of peptide mRNA were not affected by L-DOPA treatment. Loss of nigral dopamine cells in a primate species causes opposing alterations in the expression of enkephalin and substance P mRNA in the caudate nucleus and putamen. No changes were observed in the nucleus accumbens, which reflects the resistance of the mesolimbic neurons to MPTP toxicity. While the decrease in substance P mRNA was reversed by L-DOPA treatment, the increase in enkephalin mRNA was not. This may partly indicate the greater effect of L-DOPA on the direct GABA pathway compared to the indirect output pathway from the striatum.
Brain Res Mol Brain Res 1995 Sep
PMID:L-DOPA reverses altered gene expression of substance P but not enkephalin in the caudate-putamen of common marmosets treated with MPTP. 750 Aug 41

Changes in gene expression after kindled seizures were examined using microdissection of discrete brain areas and Northern and slot blot analyses. Experimental animals were kindled with either of two protocols: (1) a paradigm in which 50 Hz/10 s stimulus trains were delivered every 30 min through hippocampal electrodes (12 stimulations every other day for 4 days) and (2) a traditional approach in which 50 Hz/10 s stimulus trains were given to the hippocampus three times daily for 16 days. Rats were sacrificed 24 h or 30 days after the last kindled seizure. We first examined the possibility that kindling may affect transcription of mRNA for neurotransmitter receptors. We found significant decreases (22-58%) in AMPA/kainate activated glutamate receptor mRNAs (GluR1, -2, -3 mRNAs) in hippocampus, amygdala/entorhinal cortex and in frontoparietal cortex 24 h but not 30 days after rapidly kindled seizures. However, changes in GABA receptor alpha 1, alpha 2, alpha 4 or beta 1 mRNAs were not observed in any brain region 30 days after traditional kindling or 24 h after rapidly kindled seizures. In addition, we tested whether changes in the expression of proenkephalin could be detected after kindling. We found significant increases (1.7-10 fold) in proenkephalin mRNA in the frontoparietal cortex, hippocampus and in the amygdala/entorhinal cortex 24 h but not 30 days after rapidly kindled seizures. Our findings suggest that changes in glutamate receptor and proenkephalin gene expression are robust, acute sequelae to kindled seizures and may be involved in kindling.
Brain Res Mol Brain Res 1994 Jul
PMID:Changes in glutamate receptor and proenkephalin gene expression after kindled seizures. 752 14

A single point mutation within the GABA receptor gene Resistance to dieldrin (Rdl) confers a high level of resistance to cyclodiene insecticides in a wide range of insects. Previous studies have shown partial rescue of the susceptible phenotype via germline transformation of a 36 kb cosmid coding (or all four alternative Rdl splice forms. Here, we describe the construction of two Rdl promoter/cDNA minigenes, each coding for one of the splice forms alone. Single splice forms rescued both the insecticide susceptible and resistant phenotypes associated with the locus as effectively as the complete cosmid. The minigenes also rescue the lethality associated with homozygous re-arrangements disrupting the Rdl gene, and the level of rescue observed is not increased by the addition of more than one splice form. This demonstrates that only a single Rdl splice form is necessary both to confer insecticide sensitivity and also to rescue lethality. Methods by which phenotype rescue could be enhanced and the potential advantages of using Rdl as a selectable marker are discussed.
J Mol Biol 1995 Oct 20
PMID:GABA receptor minigene rescues insecticide resistance phenotypes in Drosophila. 756 84

The effects of acute and repeated daily cocaine on the levels of mRNA coding for glutamic acid decarboxylase (GAD), preproenkephalin (PPE), preprotachykinin (PPT), and the dopamine D2 receptor were determined in the striatum, nucleus accumbens core and shell areas (NAcore, NAshell), and medial prefrontal cortex. Rats were given repeated saline or cocaine for 6 days. A cocaine challenge administered 24 h later resulted in an augmented locomotor response in daily cocaine-pretreated rats. Six h after the challenge, rats were sacrificed and Northern blot analysis revealed that acute cocaine increased GAD mRNA levels by 44% in the NAshell, while repeated cocaine prevented the acute cocaine-induced increase. These data suggest that cocaine may differentially regulate GABA release at NA core and shell projection fields.
Brain Res Mol Brain Res 1995 Apr
PMID:Cocaine alters glutamic acid decarboxylase differentially in the nucleus accumbens core and shell. 760 27

Using polymerase chain reactions (PCR) on cDNA, the DNA sequence of a membrane spanning region of a GABA receptor of the red flour beetle, Tribolium castaneum was identified. The deduced amino acid sequence indicates that its basic structure is similar to the GABA receptor of Rdl type subunits of Drosophila melanogaster and of Blattella germanica. Particularly conserved are M1, M2 and M3 segments. Within this 146 amino acid stretch, the GABA receptor from the red flour beetle differed from corresponding ones from Drosophila and Rdl subunit of B. germanica by 12 and eight amino acids, respectively. By using an identical approach, the corresponding DNA region was sequenced from the cDNA of a cyclodiene-resistant strain of T. castaneum. While two points of mutation were found only one mutation in DNA was found to result in an amino acid shift. The site of mutation was at the 5th amino acid of the M2 cylinder where G to T conversion of the GCT codon resulted in a conversion of alanine to serine. This is qualitatively the same mutational switch of alanine to serine in resistant strains previously reported to have occurred in cyclodiene-resistant Drosophila melanogaster, Aedes aegypti and Blattella germanica, indicating that this amino acid change is the likely cause for evolution of the nerve insensitive type of resistance to cyclodiene insecticides.
Comp Biochem Physiol B Biochem Mol Biol 1995 Jul
PMID:DNA sequence and site of mutation of the GABA receptor of cyclodiene-resistant red flour beetle, Tribolium castaneum. 761 64

Chronic antihypertensive treatment with clonidine and beta-adrenoceptor blockers leads to a significant increase in GABA-A receptor number in the hypothalamus, the pons-medulla and the striatum. The enhancement of receptor number after two beta-blockers was associated with the decrease of Kd factor in the pons-medulla and the striatum. There was no change in receptor affinity after clonidine. We conclude that neurotransmission via GABA-A receptors is important for the hypotensive effects of clonidine and some beta-adrenoceptor blockers.
Res Commun Mol Pathol Pharmacol 1995 Mar
PMID:Activation of GABA-A receptor by hypotensive drugs. 762 Aug 24

1. The GABAA receptor-chloride channel complex has been shown to be modulated by a variety of chemicals. Scores of chemicals with diverse and unrelated structures augment the GABA-induced chloride current, while some other chemicals suppress the current. Certain heavy metals and a variety of polyvalent cations increase or decrease the current in a potent and efficacious manner. 2. We have studied the mechanisms whereby mercury, copper, zinc, and lanthanides modulated the GABA system by whole-cell and single-channel patch clamp techniques as applied to the rat dorsal root ganglion neurons in primary culture. 3. Mercuric chloride augmented the GABA-induced current to 115% of control at 0.1 microM and to 270% of control at 100 microM. It also generated a slowly developing inward current carried by a variety of ions. In contrast, methylmercury suppressed the GABA-induced current. The potent stimulation of the GABA system by mercuric chloride is deemed important in mercury intoxication. 4. Copper and zinc suppressed the GABA-induced current with an EC50 of 16 and 19 microM, respectively. They bound to a common site on the external surface of the GABA receptor-channel complex. 5. Lanthanum augmented the GABA-induced current with an EC50 of 230 microM by increasing the affinity of the receptor for GABA. It bound to a site on or near the external surface of the GABA receptor-channel complex which is different from the sites for GABA, barbiturates, benzodiazepines, picrotoxin, and copper/zinc. 6. Six other lanthanides with larger atomic numbers also exerted the same stimulatory effect with their efficacies increasing with the atomic number. 7. Single-channel analyses have revealed that the augmentation of whole-cell current by terbium, a lanthanide, is due to three actions: an increase in the overall mean open time, a decrease in the overall mean closed time, and an increase in the overall mean burst time.
Cell Mol Neurobiol 1994 Dec
PMID:GABA receptor-channel complex as a target site of mercury, copper, zinc, and lanthanides. 764 Dec 24


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