Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P06889 (Mol)
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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

1. The effect of lead (in vivo) on the uptake of GABA, dopamine, and histidine as a precursor of histamine in synaptosomes obtained from chronically lead-treated rats was studied. 2. Lead decreased the uptake of GABA, increased the uptake of dopamine, and did not change the uptake of histidine. These effects were independent of calcium concentration. 3. Lead administration to the rat changed the morphology of the synaptosomes, as manifested in the decreased number of synaptic vesicles and disturbed mitochondrial structure. 4. The results suggest the existence of several mechanisms of lead toxicity on uptake, related to individual neurotransmitters, which are not necessarily connected with a Pb2+/Ca2+ interaction.
Cell Mol Neurobiol 1994 Dec
PMID:Lead as an inductor of some morphological and functional changes in synaptosomes from rat brain. 764 Dec 30

4-PIOL is a structural analog of GABA that has low efficacy at GABAA receptor CI- channels and activates a nondesensitizing CI- conductance in central neurons. We investigated the biophysical mechanisms of its low efficacy in embryonic olfactory bulb neurons, which express a limited number of GABAA receptor subunit transcripts. Spectral analysis of GABA- and 4-PIOL-induced current fluctuations evoked in whole-cell recordings showed that three components with mean durations of approximately 0.7, 5, and 50 msec adequately describe the kinetics of the responses induced by both ligands. The contribution of the longest-lasting component was approximately 60% in the spectra of GABA-evoked responses but < 3% in the spectra of 4-PIOL-evoked responses. This is interpreted as a low incidence of long-lasting bursts in 4-PIOL-evoked responses. No difference was evident between the average inferred unitary conductances for 4-PIOL- and GABA-induced channels. These results at the level of the whole cell were confirmed and extended in outside-out single channel recordings. Taken together, the results indicate that the mechanism responsible for the low efficacy of 4-PIOL is the inability to produce frequent bursts of long duration.
Mol Pharmacol 1995 Aug
PMID:The low efficacy gamma-aminobutyric acid type A agonist 5-(4-piperidyl)isoxazol-3-ol opens brief Cl- channels in embryonic rat olfactory bulb neurons. 765 60

The recently discovered endogenous agonist for the cannabinoid receptor, anandamide (arachidonylethanolamide), can be formed enzymatically by the condensation of arachidonic acid with ethanolamine. 5Z,8Z,11Z-Eicosatrienoic acid (mead acid) has been found to substitute for arachidonic acid in the sn-2 position of phospholipids and accumulate during periods of dietary fatty acid deprivation in rats. In the present study, the chemically synthesized ethanolamide of mead acid was evaluated as a potential agonist at the two known subtypes of cannabinoid receptor: CB1 (central) and CB2 (peripheral). This compound was equipotent to anandamide in competing with [3H]CP55,940 binding to plasma membranes prepared from L cells expressing the human CB1 receptor and from ATt-20 cells expressing the human CB2 receptor. Mead ethanolamide was also equipotent to anandamide in inhibiting forskolin-stimulated cAMP accumulation in cells expressing the CB1 receptor. It inhibited N-type calcium currents with a lower potency than anandamide. Mead and arachidonic acid were equally efficacious as substrates for the enzymatic synthesis of their respective ethanolamides in rat and adult human hippocampal P2 membranes. Palmitic acid was not an effective substrate for the enzymatic synthesis of palmitoyl ethanolamide. Mead ethanolamide exhibits several characteristics of a novel agonist to CB1 and CB2 receptors and may represent another candidate endogenous ligand for the CB1 receptor. Due to the anticonvulsant properties of GABA and the positional similarity of L-serine to ethanolamine in membrane phospholipids, these compounds were synthetically coupled to arachidonic acid, and their resulting arachidonamides were tested as potential cannabinoid agonists. The arachidonamides of GABA and L-serine were inactive in both binding and functional assays at the CB1 receptor.
Mol Pharmacol 1995 Aug
PMID:Mead ethanolamide, a novel eicosanoid, is an agonist for the central (CB1) and peripheral (CB2) cannabinoid receptors. 765 62


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