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 effects of serotonin (5-HT), dopamine (DA), several peptides including FMRFamide and arginine vasotocin, the diterpene forskolin and Ca2+ were examined on adenylate cyclase in a particulate fraction from hearts of Aplysia californica. Enzyme activity was stimulated 6-7-fold by 5-HT (EC50, 1 microM) in the presence of GTP. Several 5-HT analogs particularly 5-methoxytryptamine and 5-methoxy-N-N-dimethyltryptamine were also active. The stimulatory action of 5-HT was antagonized by the 5-HT receptor blockers methergoline and metitepine and by the DA receptor blocker chlorpromazine. Dopamine had weak stimulatory action (EC50, 10 microM) and an efficacy relative to that of 5-HT of 0.3. The action of DA was antagonized by chloropromazine and metitepine. Several peptides including FMRFamide and arginine vasotocin had no effect on adenylate cyclase when tested over the concentration range 0.1-100 microM. The enzyme was stimulated 6-fold by the diterpene forskolin (EC50, 2 microM). 5-HT-stimulated activity was strongly inhibited by Ca2+. Calmodulin had no action on the enzyme in the presence of Ca2+.
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PMID:Stimulation of adenylate cyclase in the heart of Aplysia californica by biogenic amines. 285 32

During short-term sensitization, a simple form of nonassociative learning in Aplysia, the presentation of a single brief noxious stimulus results in enhancement of the defensive withdrawal reflex lasting minutes to tens of minutes. This behavioral plasticity involves presynaptic facilitation of synaptic transmission from the mechanosensory neurons that mediate the reflex to their central target cells. This facilitation is due to cAMP-dependent protein phosphorylation. To determine whether the time course of presynaptic facilitation might be due to a persistent increase in activity of adenylate cyclase (EC 4.6.1.1) itself, persistence of the transmitter, or yet other processes, we developed a perfused-membrane method to analyze the time course of activation of adenylate cyclase by transient stimuli. After stimulation by a pulse of stimulatory transmitter, activation of adenylate cyclase decayed within 60 sec. This finding indicates that the enzyme does not remain persistently active in the absence of transmitter and suggests that short-term retention is likely to be due to other mechanisms. Possible additional mechanisms include continued activation of the cyclase by transmitter, cellular factors extrinsic to the cyclase that prolong the time course of its activation, and persistence of processes downstream from the cyclase.
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PMID:Biochemical correlates of short-term sensitization in Aplysia: temporal analysis of adenylate cyclase stimulation in a perfused-membrane preparation. 289 99

Micropressure ejection of serotonin (5-hydroxytryptamine, 5-HT) produced excitatory responses in the L14 ink motor neurons of Aplysia that depended on the site of application. Ejection of 5-HT onto the cell body produced a slow response that showed variability in voltage sensitivity between preparations. In contrast, ejection of 5-HT onto the neuropil underneath the cell body produced a response whose amplitude was consistently a linear function of the holding potential, reversing near the predicted potassium equilibrium potential. Subsequent analyses focused on this second response. The neuropil response induced by 5-HT had a linear current-voltage relationship (reversing at ca. -80 mV), was associated with a decrease in input conductance, and was sensitive to changes in the concentration of extracellular K+. Serotonin application in artificial seawater (ASW) containing 30 mM K+ produced a response that reversed close to the altered Nernst potential for K+. The 5-HT response did not appear to be due to secondary activation of interneurons or to depend primarily on extracellular Ca2+, since ejection of 5-HT onto cells bathed in ASW containing 30 mM Co2+ produced responses comparable to, although somewhat attenuated from, those observed in ASW. Serotonin responses similar to those produced in ASW were obtained after perfusing the ganglion with ASW containing Co2+, 4-aminopyridine (4-AP), and tetraethylammonium (TEA). This suggests that the 5-HT-sensitive current is separate from the Ca2+-activated, fast, and delayed rectifying K+ currents. The 5-HT response appeared to be mediated by changes in levels of cAMP. Bath application of the phosphodiesterase inhibitors IBMX (3-isobutyl-1-methylxanthine) or Ro 20-1724, or the adenylate cyclase activator forskolin mimicked the 5-HT response by producing a slow inward current associated with a decrease in membrane conductance. Alteration of cellular cAMP metabolism modulated the response to 5-HT. Exposure of the ganglion to low concentrations of either Ro 20-1724 or forskolin potentiated the 5-HT response. Higher concentrations of these agents largely blocked the response to subsequent 5-HT applications. Bath application of the 8-bromo derivative of either cAMP or cGMP produced a slow inward current associated with a decrease in membrane conductance in cells voltage clamped at the resting potential. Responses to 5-HT were blocked, however, after exposure to 8-bromo-cAMP, but not to 8-bromo-cGMP. These results suggest that 5-HT produces a voltage-independent decrease in a steady-state potassium conductance that may be mediated by cAMP.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Analysis of decreased conductance serotonergic response in Aplysia ink motor neurons. 298 53

The potential role of cyclic nucleotides and calcium as regulators of neuropeptide biosynthesis was examined in the bag cell neurons of Aplysia, which produce and secrete a peptide egg-laying hormone (ELH). Elevated external potassium, which stimulates ELH biosynthesis, increased bag cell cAMP levels when assayed in the presence of a phosphodiesterase inhibitor. Dopamine and serotonin, which increase bag cell cAMP levels, both stimulated ELH synthesis, as did the phosphodiesterase inhibitor isobutylmethylxanthine, the specific adenylate cyclase activator forskolin, and the phosphodiesterase-resistant cAMP analogue 8-benzylthio-cAMP. The stimulatory effect on peptide biosynthesis appears to be specific for cAMP, as bag cell cGMP levels were not altered significantly by high potassium or forskolin, and 8-bromo-cGMP did not stimulate ELH synthesis. In contrast to cAMP, intracellular calcium inhibits ELH production: biosynthesis of the peptide was elevated in a 0 Ca2+/EGTA medium and reduced in the presence of the Ca2+ ionophore A23187. Synthesis was also elevated in the presence of the calmodulin inhibitor calmidazolium. Treatment of intact bag cells with 0 Ca2+/EGTA or A23187 did not alter cAMP levels significantly, suggesting that calcium exerts its effect on peptide synthesis independently of cAMP. The antagonistic effects of cAMP and calcium on ELH synthesis parallel their effects on bag cell excitability, suggesting that, in these cells, neuropeptide synthesis and secretion are co-regulated by the same intracellular messengers.
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PMID:Regulation of synthesis of the neurosecretory egg-laying hormone of Aplysia: antagonistic roles of calcium and cyclic adenosine 3':5'-monophosphate. 298 35

Although the peptidergic bag cell neurons of Aplysia are ordinarily silent, they respond to brief electrical stimulation by producing an afterdischarge of about 30 min duration. This afterdischarge is followed by a refractory period lasting many hours during which electrical stimulation either fails to initiate afterdischarges or produces discharges of much shorter duration. Previous work has demonstrated that cyclic AMP plays a role in the genesis of afterdischarge, both in intact bag cell clusters and in isolated cultured bag cells. We have now examined the hypothesis that in the refractory period either the synthesis of cyclic AMP or the response to cyclic AMP is attenuated. Direct measurements of cyclic AMP showed that cyclic AMP levels in the bag cell neurons are elevated to a similar extent after stimulation in refractory and nonrefractory clusters of neurons. We have found, however, that the response to cyclic AMP is altered during the refractory period. The electrophysiological responses of bag cell neurons were first examined in intact clusters of cells within the abdominal ganglion. Cyclic AMP levels were elevated using the adenylate cyclase activator, forskolin, in the presence of theophylline (FT). The duration of a first bag cell afterdischarge could be greatly increased if FT was added before stimulation. The duration of a stimulated second bag cell afterdischarge could also be significantly increased if FT was added within a brief period following the end of the first afterdischarge. Furthermore, at these times the addition of FT often resulted in the onset of spontaneous afterdischarges.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Peptidergic neurons of Aplysia lose their response to cyclic adenosine 3':5'-monophosphate during a prolonged refractory period. 298 38

Our previous results indicated that protein synthesis was necessary for serotonin (5-hydroxytryptamine, 5-HT) to regulate the phase of the biological clock in the Aplysia eye. Also, we showed that 5-HT appeared to increase the synthesis of a 34-kDa protein with an isoelectric point of 7.2. Subsequent studies were carried out to quantitate the effect of 5-HT on the 34-kDa protein and to examine whether the 34-kDa protein was involved in the circadian timing system. The regional specificity of the effect of 5-HT on the 34-kDa protein was investigated. The proximal portion of the eye appeared to synthesize much more of the 34-kDa protein than the distal portion. Also, 5-HT had a much larger effect on the synthesis of the 34-kDa protein in the proximal portion than in the distal portion. The proximal location of synthesis and the 5-HT effect on the synthesis of the 34-kDa protein correlate with the proximal location of cells and processes that are necessary for the expression of the circadian rhythm. The relationship between the effect of 5-HT on the circadian rhythm and the effect of 5-HT on the 34-kDa protein was also examined. As 5-HT causes phase shifts in the rhythm by activating adenylate cyclase to increase cAMP, forskolin and 8-benzylthioadenosine 3',5'-cyclic monophosphate mimicked the effect of 5-HT on the 34-kDa protein. We also found that 5-HT significantly increased the synthesis of the 34-kDa protein at phases when 5-HT delays or advances the phase of the rhythm but did not increase the synthesis of the 34-kDa protein at a phase when 5-HT did not phase shift. This phase-dependent effect of 5-HT on the 34-kDa protein qualitatively accounts for the phase dependence of the effect of 5-HT on the circadian rhythm. These results, when considered together with our earlier data, suggest that the synthesis of the 34-kDa protein is directly involved in the phase shift produced by 5-HT. The 34-kDa protein is worthy of future investigation as a candidate for a component of the circadian oscillator.
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PMID:Involvement of a specific protein in the regulation of a circadian rhythm in Aplysia eye. 302 61

Forskolin, a diterpene extracted from Coleus forskolii, stimulates the production of cAMP in a variety of cells and is potentially an important tool for studying the role of cAMP in the modulation of neuronal excitability. We studied the effects of forskolin on neurons of nudibranch molluscs and found that it caused characteristic, reversible changes in the amplitude and waveform of the transient K current, IA, and also activated an inward current similar to the cAMP-dependent inward current previously described in molluscan neurons. Forskolin altered the time course of IA activation and inactivation but did not affect the voltage dependence or the reversal potential of the current. IA normally inactivates exponentially, but in forskolin the time course of inactivation can be fit by the sum of 2 exponentials with an initial rate that is faster than the control and a final rate that is much slower. On depolarization in forskolin, IA begins to activate at the normal rate, but a slower component of activation is also seen. The changes in IA in the nudibranch cells were qualitatively different than the changes caused by forskolin in Aplysia bag cell neurons (Strong, 1984). Experiments were performed to determine whether these effects of forskolin require cAMP. Intracellular injection of cAMP, application of membrane-permeable analogs of cAMP, application of phosphodiesterase inhibitors, and intracellular injection of the active catalytic subunit of cAMP-dependent protein kinase did not affect the amplitude or waveform of IA. Also, the changes in IA that are caused by forskolin were not prevented or reversed by intracellular injection of an inhibitor of cAMP-dependent protein kinase. Cyclic AMP did, however, activate inward current at voltages near the resting potential. We conclude that the changes in IA and the activation of inward current represent separate affects of forskolin. The inward current appears to depend on an increase in intracellular cAMP, while the changes in IA do not. These experiments show that, in addition to activating adenylate cyclase, forskolin may have a separate direct affect on the transient K current.
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PMID:Forskolin's effect on transient K current in nudibranch neurons is not reproduced by cAMP. 302 41

Two experimental approaches--the cellular and the neurogenetic--to the study of molecular mechanisms of elementary memory implicate the cyclic AMP cascade in general, and adenylate cyclase in particular, in the processes of acquisition and short-term memory. Models of learning and memory should account for four basic phenomena: persistence of memory, stimulus convergence, temporal specificity and memory decay. These phenomena thus place constraints on the structure and operation of any postulated memory apparatus. The relevant experimental data derived from the study of memory mutants in Drosophila and of the gill and siphon withdrawal reflex in Aplysia are discussed and analyzed in light of the above mentioned constraints.
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PMID:Possible involvement of adenylate cyclase in learning and short-term memory. Experimental data and some theoretical considerations. 303 49

We have measured by radioimmunoassay the amount of total, free, and bound forms of cyclic AMP (cAMP) within the abdominal ganglion and in five identified cell bodies of neurons from Aplysia californica. In the abdominal ganglion the unbound (free) cAMP levels comprised approximately 25-30% of the total cAMP content under the unstimulated condition, i.e., bathed in high-magnesium saline. Under pharmacological conditions that blocked endogenous phosphodiesterase and activated adenylate cyclase, ganglionic free cAMP levels were elevated more than fourfold, while bound cAMP levels more than doubled. Freeze-substitution techniques were employed to facilitate isolation of individual cell bodies either before or after pharmacological manipulation of cAMP levels. The basal, free cAMP content of cells R2, LP1, R15, L11, and L2-L6 was in the range of 10-40 pmol/mg of cell protein, which accounted for approximately one-half of the total cAMP content per cell body. Determinations of individual cell volumes indicated that the basal, free cAMP concentrations ranged from 1 to 6 microM. Under the same pharmacological conditions that elevated ganglionic cAMP in levels, no changes were measured in either the free or the bound forms of cAMP in isolated cell bodies. Our results indicate that the cAMP elevation was compartmentalized within the neuropilar region of the ganglion, most likely within the processes of the nerve cells. Previous results demonstrated that cAMP injections into the same Aplysia neurons studied here induced a cAMP-activated sodium current, INa (cAMP). In this report we discuss the possibility that pharmacological elevation of cAMP within neuronal processes may reach concentrations similar to those produced by cAMP injections into somata.
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PMID:Compartmentalization of cyclic AMP elevation in neurons of Aplysia californica. 303 61

Recent evidence suggests that serotonin (5-HT) and a neuropeptide, small cardioactive peptideB (SCPB), exert parallel modulatory actions on neuronal and muscular function in Aplysia via changes in the levels of cAMP. We have examined the effects of both of these neurotransmitters on the adenylate cyclase activity in membrane homogenates of pleural ganglia. The results indicated that 5-HT and SCPB enhance the production of cAMP via a direct activation of adenylate cyclase. In addition, we found that the increase in cyclase activity produced by 5-HT could be selectively blocked by the S2-serotonergic antagonists, ketanserin and ritanserin. Thus, specific 5-HT receptors are present which appear to be distinct from those that mediate the effects of SCPB on the activity of adenylate cyclase.
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PMID:Evidence for separate receptors that mediate parallel effects of serotonin and small cardioactive peptideB (SCPB) on adenylate cyclase in Aplysia californica. 309 11


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