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)

In review is concerned with research done on an animal model for the hereditary neuropsychiatric disorder, Huntington's disease (HD). The neuropathology of HD involves primarily a selective degeneration of neurons with cell bodies in the striatum. Injection of kainic acid, a potent neuroexcitant structurally related to glutamic acid, into the rat striatum causes a selective neuronal degeneration resembling that of HD. Striatal cholinergic and GABAergic neurons, including their terminal projections in the substantia nigra, are affected by kainate; dopaminergic axons innervating the striatum as well as corticofugal fibers passing through the region are spared. The striatal kainate lesion has aided in the characterization of the neuronal circuitry in the nigrostriatal axis including the neuronal localization of dopamine-sensitive adenylate cyclase, neuroleptic binding sites, and GABA receptors. Studies in vivo and in vitro with kainate and its analogues suggest that the potent neurotoxicity of kainate involves a cooperative interaction between synaptically released glutamate and injected kainate on vulnerable neurons; prior destruction of cortico-striatal glutamatergic afferents attenuates kainate's neurotoxicity. The kainate model has been used to test drugs that may be of therapeutic benefit for HD. A better understanding of the mechanism of neurotoxicity of kainate may shed light on the cause of neuronal degeneration in HD.
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PMID:An animal model for Huntington's disease. 3 64

The effect of the putative amino acid transmitter, L-glutamate, on adenylate cyclase in crude membrane preparations of the rat tapeworm Hymenolepis diminuta was investigated to determine if glutamate effects the generation of the second messenger cAMP. Addition of glutamate at 10(-3) and 5.5 x 10(-9) M resulted in significant elevations in basal activity of adenylate cyclase, while concentrations in the 10(-5)-10(-7) M range caused significant depressions below basal activity. Assays with glutamate agonists and other acidic compounds showed glutamate to be the only amino acid, dicarboxylic acid, or acidic compound capable of this pattern of stimulation and inhibition. While the response of adenylate cyclase to glutamate agonists suggested that an N-methyl-D-aspartic acid (NMDA) type receptor may be present, glutamate agents acting as NMDA antagonists in vertebrate systems were agonists. Metabolic end products of glycolysis stimulated adenylate cyclase, suggesting that these, along with metabolic glutamate may regulate glycolytic enzymes. Only 10(-3) M L-glutamate significantly stimulated adenylate cyclase activity in tissue slices, and this response was restricted to those slices rich in nervous tissues. L-Glutamate eliminated the 5-hydroxytryptamine (5-HT) stimulated adenylate cyclase response suggesting that glutamate can modulate the 5-HT stimulated elevations in adenylate cyclase activity. The data support the hypothesis that L-glutamate is a neurotransmitter-modulator in the cestode.
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PMID:The effect of L-glutamate and related agents on adenylate cyclase in the cestode Hymenolepis diminuta. 170 17

Intracellular recordings from primary mechanosensory neurones (dorsal cells) in the lamprey spinal cord were used to test the membrane effects of a variety of putative neuromodulatory agents. gamma-Aminobutyric acid (GABA) produced a dose-dependent increase in the duration of mixed Na-Ca or pure Ca action potentials in these cells. L-Glutamate and glycine produced minimal broadening of Ca action potentials. Acetylcholine, noradrenaline, serotonin, met-enkephalin, D-glutamate and dopamine had no effect. The pharmacology of GABA's action appeared to be complex. While the GABAA receptor antagonists, bicuculline, picrotoxin and curare, did not block GABA's effect, both the GABAA receptor agonist, muscimol, and the GABAB-receptor agonist, baclofen, occasionally broadened Ca action potentials in these cells. GABA had no effect on the resting potential, passive current-voltage (I-V) characteristics and pure Na action potential of dorsal cells, ruling out an action on passive membrane channels, transmitter-activated channels, or on those voltage-dependent channels activated during the Na action potential. Thus, GABA affected dorsal cells only when a significant Ca current was evident. GABA appeared not to increase the conductance of the Ca channels since its action was accompanied by an increase in input resistance, suggesting an inhibition of Ca-dependent conductance that normally acts to repolarize the membrane during a Ca action potential. An inhibitory effect of GABA on a Ca-dependent Cl conductance was ruled out in experiments where the Cl gradient was altered by removal of extracellular Cl without affecting GABA-induced Ca action potential prolongation. Dorsal cells have a prominent Ca-dependent K conductance (gK(Ca], and it is this conductance that GABA may inhibit. Consistent with this was the observation that the hyperpolarizing after-potential that follows Ca action potentials in dorsal cells, which reflects gK(Ca) in these cells and whose duration is normally increased when the Ca action potential duration increases, was not prolonged when the Ca action potential was broadened by GABA. Further, the failure of GABA to prolong Ba action potentials was consistent with this proposed mechanism of action, since Ba apparently does not activate gK(Ca) in these cells. Forskolin, a specific adenylate cyclase activator, caused broadening of Ca action potentials in lamprey dorsal cells comparable in magnitude to that of GABA. Thus, an increase in intracellular cyclic AMP is a candidate for the intracellular mediator of GABA's effect on these cells.
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PMID:Prolongation of calcium action potentials by gamma-aminobutyric acid in primary sensory neurones of lamprey. 243 26

The rate of release of [3H]GABA from intact goldfish retinas was studied using a modified superfusion technique. Small, significant increases in the rate of GABA release were observed when the retinas were exposed to dopamine (DA) (100-1000 microM); however, when free Ca2+ was removed from the medium, the basal rate of GABA release was increased and DA became inhibitory. Forskolin, a non-specific stimulator of adenylate cyclase in intact cells, also inhibited GABA release in the absence of Ca2+. There was no significant effect of forskolin in the presence of Ca2+; however, (+)-butaclamol, a dopamine antagonist, increased basal GABA release under these conditions. L-glutamic acid (L-Glu) (1-10 mM) causes up to a 10-fold increase in GABA release. In the presence of Ca2+, DA did not significantly alter the effects of L-Glu; however, in the absence of Ca2+ a significant inhibition of the effects of L-Glu by DA was observed. Forskolin, on the other hand, inhibited the effects of L-Glu both in the presence and absence of Ca2+. Finally, EGTA (0.3-1 mM) produced a large release of GABA: this release was inhibited by DA, forskolin, theophylline, and 8-bromo cyclic AMP. These results suggest a model wherein DA stimulates Ca2+-dependent GABA release from one site and inhibits Ca2+-independent GABA release from another site via a cyclic AMP-mediated event.
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PMID:Dopaminergic regulation of GABA release from the intact goldfish retina. 286 28

An engineered calmodulin differs from vertebrate calmodulin in its ability to activate Bordetella pertussis adenylate cyclase, and this difference has been utilized as the basis for a new purification protocol for the adenylate cyclase. VU-8 calmodulin, in which 3 glutamic acid residues (residues 82-84) have been substituted with 3 lysine residues, has a 1000-fold lower apparent affinity for the adenylate cyclase, compared to vertebrate calmodulin, and decreased maximal activity. Because of the relatively calcium-independent nature of the interaction between calmodulin and the cyclase, the use of calmodulin-Sepharose conjugates in the purification of the cyclase requires the use of chaotropic agents for elution. However, when immobilized VU-8 calmodulin was tested as a calcium-dependent, affinity-based, adsorption chromatography step in the purification of the cyclase from culture media or bacterial extracts, the enzyme bound to the column in a calcium-dependent manner, and a nearly homogeneous enzyme was obtained in high yield. These results demonstrate the feasibility of using engineered calmodulins that have selective differences in activity for the rational design of rapid purification protocols for calmodulin-binding proteins as well as indicate the importance of the conserved negative charge cluster at residues 82-84 of calmodulin for activation of this cyclase.
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PMID:Affinity-based chromatography utilizing genetically engineered proteins. Interaction of Bordetella pertussis adenylate cyclase with calmodulin. 289 77

Electron cytochemical studies have been made of the effect of various concentrations of the glutamic acid on localisation of adenylate and guanylate cyclases in synaptosomes from the brain cortex of rats. It was found that the glutamic acid (10(-3) M) stimulates the activity of intrasynaptosomal adenylate cyclase, but does not affect postsynaptic pool of the enzyme. The effect of glutamate on guanylate cyclase results in the increase of the frequency of the reaction both in synaptosomal and postsynaptic membranes. It is suggested that in the conduction of glutamate signal, guanylate cyclase--cGMP, but not adenylate cyclase--cAMP, system may be involved, although activation of intrasynaptosomal adenylate cyclase indicates its participation in presynaptic processes.
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PMID:[Selective sensitivity of synaptosomal cyclases to glutamic acid]. 290 5

PHM, the human counterpart of porcine Peptide Histidine Isoleucine amide (PHI), is shown to be a VIP agonist with low potency on human VIP receptors located in colonic epithelial cell membranes. Its potency is identical to that of PHI but by 3 orders of magnitude lower than that of VIP itself in inhibiting 125I-VIP binding and in stimulating adenylate cyclase activity. This contrasts markedly with the behaviour of PHI on rat VIP receptors located in intestinal epithelial cell membranes where PHI is a potent agonist with a potency that is 1/5 that of VIP. In another connection, we show that 24-glutamine PHI has the same affinity as 24-glutamic acid PHI (the natural peptide) for rat or human VIP receptors. These results indicate that while PHI may exert some physiological function through its interaction with VIP receptors in rodents, its human counterpart PHM is a very poor agonist of VIP in human. Furthermore, they show that the drastic change in position 24 of PHI (neutral versus acid residue) does not affect the activity of PHI, at least on VIP receptors.
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PMID:Interaction of PHM, PHI and 24-glutamine PHI with human VIP receptors from colonic epithelium: comparison with rat intestinal receptors. 298 61

Bilateral injections of 6-OHDA in the ventral mesencephalic tegmentum (VMT) destroy the DA afferents of the nucleus accumbens but do not induce any denervation supersensitivity of the D1 receptors in the nucleus accumbens. Because other non-DA afferent fibers might also regulate D1 receptors in that structure, bilateral ablations of the prefrontal cortex were performed. This lesion induced a 55% decrease of [3H]glutamic acid high-affinity uptake activity in the nucleus accumbens. When the prefronto-cortical ablation was performed simultaneously with the bilateral injection of 6-OHDA in the VMT, a marked hypersensitivity of DA-sensitive adenylate cyclase activity was observed in the nucleus accumbens (+52% increase of Vmax and a two-fold decrease of the Kapp for DA) while the ablation of the prefrontal cortex alone induced only a +14% (P less than 0.01) increase of D1 receptors in that structure. These results indicate that the regulation of D1 receptors in the nucleus accumbens is not solely dependent on the presynaptic DA innervation and that other non-DA fibers, such as those of the cortico-nucleus accumbens pathway, might contribute to it.
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PMID:Non-DA prefronto-cortical efferents modulate D1 receptors in the nucleus accumbens. 614 86

The mu opiate receptor is a principal brain site for activities of morphine, other opiate drugs, and opioid peptides in modulating pain and altering mood. Recent cloning of cDNAs encoding rat and human mu receptors reveals charged amino acid residues within putative transmembrane domains (TMs) II, III, and VI, a substantial N-terminal extracellular domain, and a C-terminal intracellular domain. Deletion of 64 N-terminal amino acids produced little effect on receptor function (Wang, J.B., Imai, Y., Eppler, C.M., Gregor, P., Spivak, C.E., and Uhl, G.R. (1993) Proc. Natl. Acad. Sci. U.S.A. 90, 10230-10234). Further deletion of 33 C-terminal amino acids yielded a receptor at which morphine, but not the substituted enkephalin DAMGO ([D-Ala2,MePhe4,Glyol5]enkephalin), inhibited adenylate cyclase. Alanine substitution for each charged TM residue in the N-terminally deleted receptor reduced affinities for morphine, DAMGO, and the opiate antagonist naloxone. Replacement of TM II Asp114 with asparagine or glutamic acid increased mu receptor affinity for naloxone. TM II and TM III glutamic acid substitutions for Asp114 and Asp147 reduced agonist binding affinities but allowed full inhibition of adenylate cyclase at high agonist concentrations. TM VI histidine substitution with alanine yielded a receptor that produced almost twice the cyclase inhibition displayed by the wild type receptor in parallel transient expression assays. These findings underscore the importance of charged residues in TM II, III, and VI for different receptor functions and the modest involvement of extensive portions of N- and C-terminal receptor domains in these processes.
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PMID:-mu opiate receptor. Charged transmembrane domain amino acids are critical for agonist recognition and intrinsic activity. 805 Nov 54

PEC-60, a sixty-residue novel regulatory peptide with N-terminal glutamic acid and C-terminal cysteine is abundant in intestinal tissue. PEC-60-like immunoreactivity is found in catecholamine neurons and intracerebroventricular injections of PEC-60 reduce dopamine utilization within the caudate nucleus indicating a possible role of this peptide in the central nervous system. We have investigated the effect of PEC-60 on cAMP formation in membrane preparations from rat caudate nucleus. We have found that PEC-60 significantly and dose-dependently reduces basal and forskolin stimulated cAMP production. The results demonstrate for the first time the interaction of PEC-60 with specific binding sites that regulate adenylate cyclase in inhibitory fashion in rat caudate nucleus.
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PMID:PEC-60, a novel regulatory peptide reduces cyclic AMP formation in rat caudate nucleus. 826 23


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