Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:4.6.1.1 (adenylate cyclase)
19,190 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The aim of this study was to achieve a better understanding of the integration in striatal medium-sized spiny neurons (MSNs) of converging signals from glutamatergic and dopaminergic afferents. The review of the literature in the first section shows that these two types of afferents not only contact the same striatal cell type, but that individual MSNs receive both a corticostriatal and a dopaminergic terminal. The most common sites of convergence are dendritic shafts and spines of MSNs with a distance between the terminals of less than 1-2 microns. The second section focuses on synaptic transmission and second messenger activation. Glutamate, the candidate transmitter of corticostriatal terminals, via different types of glutamate receptors can evoke an increase in intracellular free calcium concentrations. The net effect of dopamine in the striatum is a stimulation of adenylate cyclase activity leading to an increase in cAMP. The subsequent sections present information on calcium- and cAMP-sensitive biochemical pathways and review the regional and subcellular distribution of the components in the striatum. The specific biochemical reaction steps were formalized as simplified equilibrium equations. Parameter values of the model were chosen from published experimental data. Major results of this analysis are: at intracellular free calcium concentrations below 1 microM the stimulation of adenylate cyclase by calcium and dopamine is at least additive in the steady state. Free calcium concentrations exceeding 1 microM inhibit adenylate cyclase, which is not overcome by dopaminergic stimulation. The kinases and phosphatases studied can be divided in those that are almost exclusively calcium-sensitive (PP2B and CaMPK), and others that are modulated by both calcium and dopamine (PKA and PP1). Maximal threonine-phosphorylation of the phosphoprotein DARPP requires optimal concentrations of calcium (about 0.3 microM) and dopamine (above 5 microM). It seems favourable if the glutamate signal precedes phasic dopamine release by approximately 100 msec. The phosphorylation of MAP2 is under essentially calcium-dependent control of at least five kinases and phosphatases, which differentially affect its heterogeneous phosphorylation sites. Therefore, MAP2 could respond specifically to the spatio-temporal characteristics of different intracellular calcium fluxes. The quantitative description of the calcium- and dopamine-dependent regulation of DARPP and MAP2 provides insights into the crosstalk between glutamatergic and dopaminergic signals in striatal MSNs. Such insights constitute an important step towards a better understanding of the links between biochemical pathways, physiological processes, and behavioural consequences connected with striatal function. The relevance to long-term potentiation, reinforcement learning, and Parkinson's disease is discussed.
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PMID:Postsynaptic integration of glutamatergic and dopaminergic signals in the striatum. 783 76

The auditory nerve serves as the only excitatory input to neurons in the avian cochlear nucleus, nucleus magnocellularis (NM). NM neurons in immature animals are dependent upon auditory nerve signals; when deprived of them, many NM neurons die, and the rest atrophy. Auditory nerve terminals release glutamate, which can stimulate second messenger systems by activating a metabotropic glutamate receptor (mGluR). Therefore, it is possible that the effectors of mGluR-stimulated signal transduction systems are needed for NM neuronal survival. This study shows that mGluR activation in NM neurons attenuates voltage-dependent changes in [Ca2+]j. Voltage-dependent Ca2+ influx was also attenuated by increasing cAMP with forskolin, VIP, or 8-bromo-cAMP, indicating that mGluR activation may stimulate adenylate cyclase. The main results may be summarized as follows. NM neurons possess high voltage-activated Ca2+ channels that were modulated by quisqualate, glutamate, and (+/-)trans-ACPD, in that order of potency. Glutamatergic inhibition of Ca2+ influx was not blocked by L-AP3 or L-AP4, which antagonize the actions of mGluRs in other neural systems; it was blocked by serine-O-phosphate. Finally, the attenuation of voltage-dependent Ca2+ influx was duplicated by cAMP accumulators. Since NM neurons have high rates of spontaneous activity and higher rates of driven activity, the expression of this mGluR turns out to be very valuable: without it, [Ca2+]j could reach lethal concentrations. These results provide an important clue as to the identity of an intracellular signal that may play an important role in NM neuronal survival.
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PMID:Glutamatergic inhibition of voltage-operated calcium channels in the avian cochlear nucleus. 789 Nov 30

The neurotoxic effect of glutamate in cultured mouse mesencephalic dopaminergic neurons was investigated. Neuron-rich cell cultures were prepared from 13-14-day-old fetal mouse ventral mesencephalic tissue. Cultures were exposed to glutamate for 10 min and evaluated for glutamate neurotoxicity (GNT) 18-24 hr later by tyrosine hydroxylase (TH) immunostaining, microtubule associated protein-2 (MAP2) immunostaining, and radiolabeled dopamine uptake assay. In glutamate-exposed cultures, the number of TH-positive neurons and the level of dopamine uptake were reduced to 40% (35-45%) and 50% (47-52%), respectively, of control cultures. The number of MAP2-positive neurons was also reduced to 47%, indicating that the GNT was not restricted or selective to dopaminergic neurons. It is concluded that GNT was mediated by the N-methyl-D-aspartic acid (NMDA) receptor from the following observations: 1) GNT was completely blocked by MK-801, an NMDA receptor antagonist; 2) NMDA itself was as toxic as glutamate; 3) 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX), an antagonist of the alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid/kainate (AMPA/KA) receptor, did not block GNT; 4) kainate did not show neurotoxicity at a low concentration; and 5) two modulators of the NMDA receptor, 7-chlorokynurenic acid and magnesium, were effective in blocking GNT. Protective effects of phorbol myristate acetate, a tumor promoter, and gangliosides (GM1 and GT1b) on GNT were also demonstrated. Possible interactions between GNT and several protein kinase cascades were also investigated. Forskolin, an activator of adenyl cyclase and protein kinase A, showed some protective effect on GNT. But okadaic acid, an inhibitor of phosphatases, and genistein, a tyrosine kinase inhibitor, did not show any protective effect. These results suggest that 1) glutamate is capable of causing neuronal death in the substantia nigra; 2) GNT on dopaminergic neurons is mainly mediated by the NMDA receptor under the conditions of our study; 3) protein kinase C translocation is a key mechanism of GNT; and 4) there is an interplay of a signal transduction system in the pathomechanism of GNT.
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PMID:Glutamate neurotoxicity in mesencephalic dopaminergic neurons in culture. 790 39

The transmitter glutamate is thought to be used by all vertebrate photoreceptors to drive the second-order neurons of the retina, horizontal and bipolar neurons. Dopamine, an endogenous retinal neurotransmitter localized to amacrine and interplexiform cells, has previously been shown to enhance glutamate-gated currents in retinal horizontal cells. In the present study we demonstrate that bipolar cells, like horizontal cells, possess glutamate receptors that are modulated by dopamine. We then identify some components of the pathway through which dopamine acts. We used whole-cell patch recording to measure how bath-applied dopamine modulated the currents elicited by puffs of transmitter solutions at bipolar cell dendrites. Excitatory amino acid-gated currents were evoked by pressure ejecting 1 mM glutamate or 10 microM kainate for 40 msec through a micropipette positioned at the dendrites of bipolar cells. Bath-applied dopamine (20 microM) enhanced the response to glutamate in OFF bipolar cells in the retinal slice by 40% and in isolated OFF bipolar cells by 65%. We also explored the components of the intracellular pathway mediating this modulation. Response enhancement was blocked by the D1 receptor antagonist SCH23390, but not by the D2 receptor antagonist spiperone, suggesting that the enhancement by dopamine is mediated by a D1 receptor. GDP-beta-S, a G-protein inactivator, blocked the enhancing action of dopamine, suggesting that the D1 receptor activated a G-protein to enhance the glutamate-gated current. Both 8-(4-chlorophenylthio)adenosine, a cAMP analog, and the addition of the catalytic subunit of protein kinase A (PKA) to the recording pipette enhanced glutamate-gated currents, while H-7, a PK inactivator, and PKI20amide, a PKA-specific inhibitor, blocked the enhancing action of dopamine. These data suggest that dopamine acts at D1 receptors in the dendrites of bipolar cells to activate adenyl cyclase, which through cAMP enhances a glutamate-gated current in bipolar cell dendrites. Thus, dopamine may modulate synaptic transmission from photoreceptors to OFF bipolar cells.
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PMID:Dopamine enhances a glutamate-gated ionic current in OFF bipolar cells of the tiger salamander retina. 793 65

Consequent to agonist exposure, many G protein-coupled receptors undergo sequestration or internalization. Results with receptors linked to adenylate cyclase, such as the beta 2-adrenergic receptor, or receptors linked to phospholipase C (PLC) have provided conflicting results regarding the role of second messenger-dependent (i.e., protein kinase A or C) and -independent (i.e., beta-adrenergic receptor kinase) kinases in mediating this process. Recent results for truncated and mutated gastrin-releasing peptide (GRP) receptors (GRP-R), as well as muscarinic cholinergic receptors, suggest that activation of protein kinase C may be needed for full receptor internalization. Nearly all G protein-coupled receptors studied to date, including the GRP-R, possess two highly conserved amino acids that are important in mediating receptor-G protein coupling to second messengers, i.e., arginine in the proximal second intracellular loop and alanine in the distal third intracellular loop. We selectively mutated each of these residues in the GRP-R to determine their importance for activation of PLC. Site-directed mutagenesis was performed to change arginine at position 139 to glycine (R139G mutant) and alanine at position 263 to glutamate (A263E mutant), with stable cell lines being created by transfection of the wild-type or mutated receptor cDNA into BALB/3T3 fibroblasts. Both R139G (Kd = 12.0 +/- 1.6 nM) and A263E (Kd = 12.2 +/- 1.7 nM) had a lower affinity for bombesin than did wild-type GRP-R (Kd = 1.4 +/- 0.4 nM); however, characteristic stoichiometries for the binding of agonists to this receptor were maintained equally in all three cell lines (bombesin > GRP >> neuromedin B). The wild-type GRP-R exposed to bombesin increased [3H]inositol phosphates (a measure of PLC activation) approximately 4-fold, with an EC50 of 5.1 +/- 2.2 nM. In contrast, [3H]inositol phosphates were not significantly increased in cells expressing R139G or A263E receptors, demonstrating that Arg139 and Ala263 are required for GRP-R activation of PLC. However, when receptor internalization at 37 degrees was assessed by ligand acid-stripping studies, 53 +/- 2% of A263E receptors were internalized at 90 min, compared with 85 +/- 5% of wild-type GRP-R, whereas only 10 +/- 3% of R139G receptors were internalized. Preincubation of either mutant cell line with 100 nM 12-O-tetradecanoylphorbol-13-acetate markedly increased internalization rates, such that at 90 min 62 +/- 2% of R139G receptors and 82 +/- 1% of A263E receptors were internalized.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Internalization of the gastrin-releasing peptide receptor is mediated by both phospholipase C-dependent and -independent processes. 793 30

Excitatory amino acid neurotransmission is an essential component of the neuroendocrine transmission line that regulates anterior pituitary luteinizing hormone (LH) and follicle-stimulating hormone (FSH) secretion. Excitatory amino acids (EAAs), such as glutamate and aspartate, are found in large concentrations in presynaptic boutons of a variety of important hypothalamic nuclei, including the arcuate nucleus, the suprachiasmatic nucleus, the supraoptic nucleus, the paraventricular nucleus, and the preoptic area. EAA receptors can be divided into two broad groups, namely, ionotropic and metabotropic receptors. Ionotropic receptors are subdivided into NMDA (N-methyl-D-aspartate), kainate, and AMPA (DL-alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid) receptors. Their main mode of action is by the modulation of Na+, K+, and Ca2+ ion channels. Metabotropic receptors, on the other hand, act by a G-protein-stimulated release of intracellular Ca2+ or modulation of adenylate cyclase activity. The different EAA receptor subtypes are found in a variety of areas of the hypothalamus and the brain. In a variety of species, the administration of glutamate, NMDA, or kainate leads to LH release mediated through the stimulation of hypothalamic gonadotropin hormone-releasing hormone (GnRH) release. The major site of NMDA action appears to be the preoptic area--where GnRH cell bodies reside. AMPA and kainate appear to act primarily at the arcuate nucleus/median eminence, the site of GnRH nerve terminals. NMDA may also act upon noradrenergic neurons in the locus coeruleus to influence hypothalamic GnRH release. The steroid-induced LH surge in ovariectomized animals and the preovulatory surge of LH in cycling animals and in pregnant mare's serum gonadotropic-primed animals are blocked by the NMDA antagonist MK801 and the AMPA/kainate antagonist DNQX. MK801 also suppressed FSH surges in most instances, whereas DNQX had no effect on FSH surges. In the ovariectomized female rat, both the NMDA antagonist AP5 and the AMPA/kainate antagonist DNQX, lowered mean LH levels, LH pulse amplitude, and LH pulse frequency. Activation of NMDA receptors advanced the time of vaginal opening in the immature female rat, while kainate and DNQX were without effect. Gonadal steroid removal (castration) did not alter NMDA receptor levels or affinity in the hypothalamus of female or male rats. Likewise, steroid replacement to castrate rats did not affect hypothalamic NMDA receptor levels or NMDA R1 mRNA levels. Similarly, NMDA and kainate receptor levels in the hypothalamus did not change during the time of puberty in the female rat. In contrast, AMPA receptor (GluR1) immunoreactive levels in the magnocellular preoptic area (mPOA), the arcuate nucleus (ARC), and the suprachiasmatic nucleus (SCN) were found to be markedly elevated during the time of the LH surge in estradiol-progesterone-treated castrate rats compared to those of the vehicle-only-treated castrate rat. The release rates of glutamate and aspartate in the POA were found to be significantly elevated during the steroid-induced LH surge in the ovariectomized adult rat.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Excitatory amino acids: function and significance in reproduction and neuroendocrine regulation. 795 68

The adenylate cyclase system has been implicated in taste transduction. The purpose of this study was to determine whether application of modulators of the adenylate cyclase system to the tongue alter taste responses. Integrated chorda tympani (CT) recordings were made in gerbils to bitter, sweet, salty, sour, and glutamate tastants before and after a 4-min application of four types of modulators of the adenylate cyclase system. The four types of modulators tested were: a) NaF, a compound that promotes dissociation of GTP binding protein; b) forskolin, a powerful stimulant of adenylate cyclase; c) 8-bromoadenosine 3' :5'-cyclic monophosphate sodium salt (8BrcAMP) and N6,2'-O-dibutyryl-adenosine 3' :5'-cyclic monophosphate sodium salt (DBcAMP), two membrane permeable forms of cAMP; and d) 1-(5-isoquinolinylsulfonyl)-2-methylpiperazine dihydrochloride (H-7) and N-(2-[methylamino]ethyl)-5-isoquinolinesulfonamide dihydrochloride) (H-8), which are protein kinase inhibitors. The tast compounds tested were: NaCl (30 mM), monosodium glutamate-MSG (50 mM), sucrose (30 mM), HCl (5 mM and 10 mM), KCl (300 mM), quinine HCl (30 mM), MgCl2 (30 mM), erythromycin (0.7 mM and 1 mM), HCl (5 mM and 10 mM), and urea (2 M). The main findings were as follows. NaF (20 mM) significantly inhibited responses to bitter compounds up to 35% and enhanced the response to sucrose by 30%. NaCl (20 mM), used as a control for NaF, inhibited most responses up to 78% with no enhancement of sucrose as seen with NaF. 8BrcAMP (1.16 mM) reduced the responses to bitter-tasting quinine HCl, MgCl2, and erythromycin but not to urea.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Modulators of the adenylate cyclase system can alter electrophysiological taste responses in gerbil. 797 5

In G protein-coupled receptors, neurotransmitter-induced binding of GTP to G proteins triggers the activation of effector systems while simultaneously decreasing the affinity of the transmitter for its specific binding site within the receptor-G protein complex. In the present study we show that, in the chick optic tectum, guanine nucleotides inhibit the binding of the glutamate analog, kainate, and activate adenylate cyclase by different mechanisms and acting on different sites. GMP-PNP, a non-hydrolyzable analog of GTP, binds tightly to G proteins so that the binding is stable even after exhaustive washing. By use of this property, we have prepared membrane samples in which G protein GTP-binding sites are pre-saturated with GMP-PNP. Experiments carried out with these membranes show that GMP-PNP, GDP-S and GMP inhibit the binding of [3H]kainate by interacting with site(s) unrelated to G proteins, whereas GMP-PNP activates adenylate cyclase activity by binding to G proteins.
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PMID:Differential effects of guanine nucleotides on kainic acid binding and on adenylate cyclase activity in chick optic tectum. 798 2

The effect of cannabinoids on phosphoinositide metabolism stimulated by activation of muscarinic receptors, alpha 1-adrenoceptors or glutamate receptors was examined in rat hippocampal cultures. Carbachol stimulated phosphoinositide turnover by 5.5-fold over basal level, whereas glutamate and norepinephrine stimulated phosphoinositide turnover by 2-fold. Addition of cannabinoids, such as delta 8-tetrahydrocannabinol, delta 9-tetrahydrocannabinol or the psychoinactive cannabidiol inhibited formation of inositol phosphates evoked by carbachol, glutamate or norepinephrine by 55-90%. The cannabinoids alone only slightly inhibited the basal unstimulated formation of inositol phosphates. The inhibitory effect of the cannabinoids was dose-dependent and was achieved within the range of pharmacologically relevant concentrations. IC50 values for delta 8-tetrahydrocannabinol, delta 9-tetrahydrocannabinol and cannabidiol were 9.6 +/- 1.0, 9.7 +/- 0.3 and 7.9 +/- 0.4 microM, respectively. Pretreatment with pertussis toxin (100 ng/ml, 18 h) did not affect the carbachol-induced stimulation of phosphoinositide turnover or its inhibition by the cannabinoids. This suggests that the inhibition by the cannabinoids of the stimulated formation of inositol phosphates is not mediated through a pertussis toxin-sensitive GTP-binding protein nor through the known effect of the cannabinoids on adenylate cyclase inhibition.
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PMID:Cannabinoids inhibit agonist-stimulated formation of inositol phosphates in rat hippocampal cultures. 810 6

L-serine-O-phosphate (L-SOP) has been reported to antagonize phosphoinositide (PI) hydrolysis in slices of rat brain as stimulated by agonists of the metabotropic glutamate receptor (mGluR). In the present study, the affinity of L-SOP was examined in a baby hamster kidney (BHK) cells expressing subtype mGluR1 or mGluR4 of the mGluR family. L-SOP or D-SOP (3 mM) did not inhibit PI-hydrolysis as stimulated by 10 microM glutamate in BHK cells expressing mGluR1. However, L-SOP was a potent agonist at the mGluR4 subtype (IC50 = 4.4 +/- 1.4 microM), which is negatively coupled to adenylate cyclase, while D-SOP was weakly active (IC50 = 1260 +/- 190 microM).
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PMID:Serine-O-phosphate has affinity for type IV, but not type I, metabotropic glutamate receptor. 810 6


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