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:3.1.4.1 (phosphodiesterase)
18,767 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The relationship between long-term electrical activity and protein phosphorylation was investigated in single, identifiable neurons in the abdominal ganglion of Aplysia californica by the intracellular injection of radiolabeled ATP followed by sodium dodecyl sulfate (SDS) gel electrophoresis. Natural and pharmacological treatments that alter the impulse activity of neurons L6 and R15 for prolonged periods did not appear to affect the phosphorylation of most of the 15 major phosphoproteins examined in these cells. Long-term excitation of L6 induced by the phosphodiesterase inhibitor IBMX correlated with phosphorylation of a 29,000-dalton protein. Long-term inhibition of L6 induced by afterdischarge of peptidergic bag-cell neurons appeared to cause dephosphorylation of a 29,000-dalton protein. Burst augmentation of R15 induced by bag-cell afterdischarge did not cause detectable changes in the phosphorylation of the major proteins we examined. These data are consistent with other studies of neural and nonneural tissues which have found a correlation between activity and the level of phosphorylation of a 29,000-dalton protein.
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PMID:Activity-related changes in protein phosphorylation in an identified Aplysia neuron. 241 15

In the preceding paper (Kehoe, 1985) it was shown that the firing of any one of three neurones (I, II, III) presynaptic to the medial cells of the pleural ganglion of Aplysia californica causes a diminution of the cholinergically controlled K conductance in those cells. Firing of the same three presynaptic neurones was shown here to cause a similar diminution in a depolarization-induced K-dependent conductance in the same post-synaptic cells. The depolarization-induced K conductance was found to disappear when Ca ions were removed from the sea water bathing the ganglion or when the cell was injected with the Ca chelator ethyleneglycol-bis-(beta-aminoethylether)N,N'-tetra-acetic acid (EGTA). The diminution in this Ca-activated, K-dependent current occurred even when the presynaptic neurone was fired a few seconds after the end of the depolarizing voltage step to the post-synaptic neurone, showing that the diminution in K conductance was not an indirect effect of a transmitter-induced diminution in Ca influx during the depolarizing pulse. The two K conductances affected by the 'blocking neurones' could be selectively eliminated. The cholinergic conductance could be blocked by receptor-specific cholinergic antagonists (e.g. 1 mM concentrations of phenyltrimethylammonium (PTMA), choline and tetraethylammonium (TEA]. Even at 10 mM concentrations, none of these compounds (including TEA, which is known to block certain Ca-activated K conductances) had an effect on the depolarization-induced, Ca-activated K conductance studied here. This latter conductance, on the other hand, was selectively blocked by an intracellular injection of EGTA. The three blocking neurones continued to diminish the K conductance (cholinergic or depolarization induced) that remained intact under these different experimental conditions. The depolarization-induced influx of Ca was shown to block the cholinergically controlled K conductance, but Ca was excluded as the possible mediator of the diminution in K conductance caused by the three blocking neurones. An intracellular injection of Ca ions into the medial cells was shown to activate a variety of changes in membrane conductance; in particular, two K-conductance increases: an early, TEA-sensitive one, and a slowly developing, TEA-insensitive one. Both the permeant cyclic AMP analogue p-chlorophenylthioadenosine 3',5'-monophosphate (CPT-cyclic AMP) and the phosphodiesterase inhibitors amino-phylline and isobutyl-1-methylxanthine (IBMX) were shown to block the depolarization-induced K conductance, and to reduce, though not eliminate, the slowly developing K conductance activated by an intracellular injection of Ca.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Synaptic block of a calcium-activated potassium conductance in Aplysia neurones. 241 50

The neurosecretory bag cell neurons of the mollusk, Aplysia, control egg-laying behavior in the animal. In these cells, elevation of cAMP greatly enhances the height and width of action potentials. A similar enhancement of action potentials is seen during the bag cell afterdischarge, a 30 min period of repetitive activity that may be triggered by peptides from the reproductive tract or by brief extracellular stimulation. The enhancement of action potentials during an afterdischarge is well correlated with the observed elevations of cAMP. In the present study, we have examined the effects of forskolin (an activator of adenylate cyclase) and theophylline (a phosphodiesterase inhibitor) on the delayed outward currents that are likely to control repolarization of the action potential. Isolated bag cell neurons, maintained in primary culture, were studied with a whole-cell patch clamp technique. High intracellular concentrations of EGTA were used to block potassium current activated by calcium entry. Analysis of the remaining voltage-dependent delayed outward current revealed two major components, which could be separated on the basis of their different kinetic properties. Both currents (IK1 and IK2) were carried by potassium. IK1, which did not inactivate during 100 msec depolarizations, was reduced in amplitude by application of forskolin and theophylline. Ik2, a current defined by its faster kinetic properties, partially inactivated during 100 msec depolarizations. This inactivation was markedly speeded by application of forskolin and theophylline. It is suggested that such changes in outward current in response to cAMP could explain the enhancement of spike width seen during an afterdischarge in vivo.
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PMID:Multiple components of delayed potassium current in peptidergic neurons of Aplysia: modulation by an activator of adenylate cyclase. 242 Sep 48

Bath application of 5-HT, at concentrations below 10 microM, enhances the amplitude of the interburst hyperpolarization in the Aplysia bursting pacemaker neuron R15. It is known that 5-HT acts via cyclic AMP to produce this effect by increasing the inwardly rectifying potassium current (IR). Here, we report that further elevating the concentration of 5-HT produces an enhancement of the depolarizing phase of the burst cycle that can eventually lead to tonic spiking activity. Voltage-clamp studies reveal that high concentrations of 5-HT continue to increase IR and, in addition enhance a voltage-gated inward current active near the action potential threshold. Pharmacological treatments and ion substitution experiments demonstrate that the inward current increased by high concentrations of 5-HT is a subthreshold calcium current (ICa). The 5-HT-induced increase in ICa is mimicked by bath application of the adenylate cyclase activator forskolin or injection of 8-bromo-cyclic AMP and is potentiated by the phosphodiesterase inhibitor isobutylmethylxanthine. It is concluded that 5-HT, acting via the second messenger cyclic AMP, can increase both potassium and calcium currents in neuron R15. It is also shown that the 5-HT-induced increase in these 2 opposing voltage-gated currents not only produces complex changes in bursting activity, but also dramatically alters R15's response to inhibitory and excitatory stimuli.
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PMID:Serotonin acting via cyclic AMP enhances both the hyperpolarizing and depolarizing phases of bursting pacemaker activity in the Aplysia neuron R15. 245 15

Voltage-clamp methods were employed to study the effects of serotonin (5-HT) and dopamine on the pharmacologically isolated calcium current in the identified Aplysia neuron R15 grown in cell culture. Neurons were obtained from juvenile animals and had not yet developed the bursting pacemaker pattern of activity characteristic of R15 in mature animals. In R15 5-HT elicits a biphasic response consisting of excitatory depolarization followed by an inhibitory hyperpolarization and dopamine elicits an inhibitory hyperpolarization. 5-HT increased the Ca2+ current without affecting its voltage dependence. The 5-HT effect persisted when Ba2+ was employed to carry current through Ca2+ channels. 5-HT did not affect the rate of Ca2+-dependent Ca2+ current inactivation other than through its effect on the magnitude of the Ca2+ current. The adenylate cyclase activator forskolin, in the presence of a phosphodiesterase inhibitor, also increased the magnitude of the Ca2+ or Ba2+ current. This result suggested that the 5-HT-induced enhancement of Ca2+ current was mediated by cAMP. Dopamine inhibited Ca2+ current when either Ca2+ or Ba2+ was employed as the current carrier. Dopamine did not affect the rate of Ca2+-dependent inactivation of Ca2+ current other than through its effect on the magnitude of the Ca2+ current. Intracellular injection of the Ca2+ chelator EGTA inhibited serotonergic modulation of the Ca2+ current but not dopaminergic modulation. These results indicated that the putative neurotransmitters 5-HT and dopamine may regulate bursting activity in mature R15 neurons through modulation of Ca2+ current.
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PMID:Reciprocal modulation of calcium current by serotonin and dopamine in the identified Aplysia neuron R15. 245 75

alpha-Bag cell peptide (alpha-BCP), one of the multiple secretory products of the precursor to the egg-laying hormone (proELH) produced by the neurosecretory bag cells of Aplysia, has been variously claimed to have excitatory or inhibitory feedback effects on the cells which secrete it and to exert some of these effects via a reduction in cAMP levels. Since it was shown previously that proELH synthesis is modulated by cAMP, the present study was undertaken to determine if alpha-BCP causes parallel alterations in cAMP levels and peptide synthesis. The peptide had no effect on bag cell levels of cAMP in the absence of stimulation and no effect on the elevation of this nucleotide by the phosphodiesterase inhibitor, isobutylmethylxanthine. However, it reduced the elevations induced by forskolin, dopamine, and high external potassium. Consistent with the above and with the hypothesis that proELH synthesis is accelerated by cAMP, alpha-BCP reduced proELH synthesis and cAMP production in parallel in forskolin-stimulated preparations, but did not inhibit stimulation of peptide synthesis by isobutylmethylxanthine or zero external Ca2+. These results support an autoinhibitory role for alpha-BCP in modulating bag cell discharge and suggest a mechanism by which it can mediate negative feedback inhibition of proELH biosynthesis.
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PMID:Alpha bag cell peptide reduces stimulated cAMP levels and pro-ELH synthesis in bag cells. 246 21

Release of the neuropeptide egg-laying hormone (ELH) from Aplysia bag cell neurons augments the endogenous bursting pacemaker activity of neuron R15. We have studied the ionic mechanisms underlying the effect of ELH in voltage-clamped R15 neurons. Both electrical discharge of the bag cells, which releases endogenous ELH, and application of synthetic ELH on cell R15 result in an increase in two discrete ionic currents. One of these currents activates with hyperpolarization, reverses near the K+ equilibrium potential, is sensitive to the external K+ concentration, and is blocked by addition of 5 mM Rb+ or 1 mM Ba2+ to the bathing medium. This current appears to be identical to the inwardly rectifying K+ current IR. The other current activates with depolarization and is blocked by replacement of external Ca2+ with Co2+ or Mn2+. This current appears to be a voltage-gated Ca2+ current ICa. Both ICa and IR in R15 have previously been shown to be enhanced by the neurotransmitter serotonin, acting via intracellular cyclic AMP. We now report that increasing cyclic AMP in R15, by applying either serotonin or the adenylate cyclase activator forskolin together with a phosphodiesterase inhibitor, mimics and occludes the action of ELH on neuron R15. Furthermore, application of ELH increases the cyclic AMP content of single R15 neurons, as measured by radioimmunoassay. Finally, the effects of ELH are potentiated by a phosphodiesterase inhibitor. These results suggest that ELH augments bursting activity in R15 by causing cyclic AMP-mediated increases in IR and ICa.
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PMID:Augmentation of bursting pacemaker activity by egg-laying hormone in Aplysia neuron R15 is mediated by a cyclic AMP-dependent increase in Ca2+ and K+ currents. 281 71

Brief electrical or hormonal stimulation of the bag cell neurons of Aplysia triggers a long-lasting discharge during which alpha bag cell peptide (alpha-BCP) and other neuropeptides are released from the cells. We have carried out experiments, using both intact abdominal ganglia and isolated neurons, demonstrating that alpha-BCP acts directly on the bag cell neurons to influence cAMP levels and voltage-dependent potassium currents. Exposure of the bag cell neurons within intact ganglia to alpha-BCP, at concentrations greater than 1 nM, inhibited an ongoing discharge. alpha-BCP also significantly reduced both basal and forskolin-stimulated levels of cAMP in bag cell clusters. The inhibition of the discharge by alpha-BCP could be prevented and reversed by pharmacological elevation of intracellular cAMP levels. Immunohistochemical staining of neurons maintained in cell culture showed that all isolated bag cell neurons exhibit immunoreactivity with antisera against alpha-BCP. Application of the adenylate cyclase activator forskolin to such isolated cells, in the presence of a phosphodiesterase inhibitor, attenuates the amplitude of the delayed voltage-dependent outward currents measured in voltage-clamp experiments. Pretreatment of the cells with alpha-BCP significantly reduced the ability of forskolin to attenuate these currents, demonstrating that alpha-BCP acts directly at autoreceptors on bag cell neurons. Experiments with the isolated cells showed that a second autoreceptor-mediated effect of alpha-BCP was the enhancement of an inwardly rectifying potassium current that was activated at potentials more negative than -40 mV. The reversal potential and conductance of the current induced by alpha-BCP were dependent on the external K+ concentration. This response to alpha-BCP could be blocked by rubidium, cesium, and barium ions. Our data demonstrate that alpha-BCP can exert inhibitory biochemical and electrophysiological actions on the bag cell neurons that release it and suggest that autoreceptors for alpha-BCP play an important role in the termination of a discharge in the bag cell neurons.
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PMID:Alpha bag cell peptide directly modulates the excitability of the neurons that release it. 282 16

In the preceding paper (Kramer and Levitan, 1988), we presented evidence that an inwardly rectifying K+ current (IR) is inactivated by Ca2+ influx accompanying spontaneous bursting activity in the Aplysia neuron R15. In this paper we examine the mechanism that enables Ca2+ to inactivate IR. Since IR is enhanced by cyclic AMP in neuron R15 (Drummond et al., 1980; Benson and Levitan, 1983), we examined the Ca2+-dependent inactivation of IR after application of either serotonin (5-HT), the adenylate cyclase activator forskolin, or a membrane-permeable cAMP analog, all agents that increase cAMP and hence the magnitude of IR. Even though more active IR channels are available under these conditions, less Ca2+-dependent inactivation is observed. This is contrasted with the Ca2+-dependent inactivation of the voltage-gated Ca2+ current (ICa). Elevating cAMP enhances ICa in R15 and also increases its Ca2+-dependent inactivation. Hence the mechanisms whereby Ca2+ inactivates IR and ICa appear to differ from each other. Elevating internal Ca2+ by repeatedly depolarizing the neuron suppresses the response of IR to brief applications of 5-HT, and speeds the relaxation of the response, suggesting that Ca2+ can interfere with the cAMP-dependent activation of IR. One biochemical site where Ca2+ can reduce cellular cAMP is by activating the Ca2+/calmodulin-sensitive form of phosphodiesterase. We have detected such enzyme activity in homogenates of Aplysia abdominal ganglia and extracts of single R15 somata. Inhibitors of the phosphodiesterase activity suppress the Ca2+-dependent inactivation of IR. Finally, we have used a radioimmunoassay to measure cAMP in individual R15 somata, and have found that R15 neurons hyperpolarized for prolonged periods contain more cAMP than do R15 neurons allowed to burst, consistent with the hypothesis that Ca2+ influx reduces cAMP.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Mechanism of calcium-dependent inactivation of a potassium current in Aplysia neuron R15: interaction between calcium and cyclic AMP. 283 52

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


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