Independent control of channel closure and block of open channels by methylxanthines at acetylcholine receptors in frog.

Silinsky, Eugene M.; Vogel, Stephen M.

doi:10.1113/jphysiol.1987.sp016684

Cited by 9 publications

(4 citation statements)

References 23 publications

(35 reference statements)

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“…Specifically, a balance between phosphorylation near the membrane and phosphorylation of more distal sites appears to determine whether a cyclic AMP analogue will produce excitation or inhibition. Based upon these results and previous results with PDE inhibitors (Silinsky, 1984;Silinsky & Vogel, 1987;Dryden et al, 1988), it is likely that the more distal of these mechanisms, i.e. the one responsible for the excitatory effects of cyclic AMP, possesses the greatest capacity to influence the secretory process.…”

Section: Discussion Cyclic Amp and Compartmentationsupporting

confidence: 62%

The role of cyclic AMP and its protein kinase in mediating acetylcholine release and the action of adenosine at frog motor nerve endings

Hirsh

Silinsky

Solsona

1990

British J Pharmacology

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1 The importance of adenosine 3': 5'-cyclic monophosphate (cyclic AMP) and its protein kinase (protein kinase A, PKA) in promoting acetylcholine (ACh) release was studied at frog motor nerve endings. The effects of cyclic AMP-dependent protein phosphorylation on the action of adenosine receptor agonists were also investigated. 2 Cyclic AMP was delivered to a local region of the cytoplasm just beneath the plasma membrane of motor nerve endings using phospholipid vesicles (liposomes) as a vehicle. Cyclic AMP in liposomes produced a parallel reduction in the mean level of evoked ACh release (m) and spontaneous ACh release (miniature endplate potential frequency; m.e.p.pf) in most experiments. These inhibitory effects of cyclic AMP on quantal ACh release resemble the action of adenosine. 3 The effects of global increases in cytoplasmic cyclic AMP concentrations using lipophilic cyclic AMP analogues were generally different from those observed with cyclic AMP. 8-(4-Chlorophenylthio) cyclic AMP (CPT cyclic AMP) produced approximately two fold increases in m and m.e.p.p.f. Dibutyryl cyclic AMP (db cyclic AMP) also increased m and m.e.p.p.f, with the effect on m being smaller and more variable. 4 All three cyclic AMP analogues reduced the effects of adenosine receptor agonists on spontaneous and evoked ACh release. 5 The roles of protein phosphorylation in mediating ACh release and the inhibitory effects of adenosine were studied with the protein kinase inhibitor H7. H7 (3O-100,uM) produced no consistent effect on evoked or spontaneous ACh release. At these concentrations, however, H7 exerted an unfortunate inhibitory action on the nicotinic ACh receptor/ion channel. 6 H7 prevented the increases in spontaneous ACh release produced by CPT cyclic AMP (250pM). Thus H7 is likely to inhibit PK A in frog motor nerve endings. 7 H7 did not alter the inhibitory effect of adenosine on evoked and spontaneous ACh release. 8 The results suggest: (i) that the adenylyl cyclase-cyclic AMP-PK A system is compartmentalized within the motor nerve terminal, (ii) that phosphorylation does not play a major role in ACh release and (iii) the cyclic AMP-PK A system modulates rather than mediates the inhibitory effects of adenosine.

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Section: Discussion Cyclic Amp and Compartmentationsupporting

confidence: 62%

The role of cyclic AMP and its protein kinase in mediating acetylcholine release and the action of adenosine at frog motor nerve endings

Hirsh

Silinsky

Solsona

1990

British J Pharmacology

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“…In the present work IBMX increased the amplitude of e.p.ps, an effect that might be related to its ability to antagonize endogenous adenosine which tonically inhibits transmission at the rat diaphragm neuromuscular junction. In contrast, at the frog sartorius neuromuscular junction, IBMX does not antagonize the adenosine receptor (Ribeiro & Sebastiao, 1985) and in submillimolar concentrations has postsynaptic inhibitory effects on transmission (Ribeiro & Sebastiao, 1987), that are probably related to its ability to block the opening of acetylcholine receptors and to increase the rate constant of receptor closure (Silinsky & Vogel, 1987). Whether the apparently different behaviour of IBMX against the adenosine receptors at the rat diaphragm and frog sartorius neuromuscular junctions reflects different sensitivities of both species to IBMX itself, rather than differences in the adenosine receptor cannot be answered in the present investigation.…”

Section: Discussionmentioning

confidence: 87%

On the adenosine receptor and adenosine inactivation at the rat diaphragm neuromuscular junction

Sebastião

Ribeiro

1988

British J Pharmacology

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1 The effects of adenosine and adenosine analogues 2-chloroadenosine (CADO), L-N6-phenylisopropyladenosine (L-PIA), D-N6-phenylisopropyladenosine (D-PIA), N6-cyclohexyladenosine (CHA) and 5'-N-ethylcarboxamide adenosine (NECA) on evoked endplate potentials (e.p.ps) and on twitch tension were investigated in innervated diaphragms of the rat. 2 Adenosine and its analogues decreased, in a concentration-dependent manner, the amplitude of both the e.p.ps and the twitch responses evoked by nerve stimulation. The order of potency in decreasing the twitch tension was CHA, L-PIA, NECA > D-PIA > CADO > adenosine. L-PIA was about 8 times more potent than D-PIA. Neither adenosine nor the adenosine analogues affected the twitch responses of directly stimulated tubocurarine-paralysed muscles. 3 8-Phenyltheophylline (8-PT), theophylline and isobutylmethylxanthine (IBMX), in concentrations virtually devoid of effect on neuromuscular transmission, antagonized the inhibitory effect of 2-chloroadenosine. The order of potency of the alkylxanthines as antagonists of the adenosine receptor at the rat diaphragm neuromuscular junction was 8-PT > IBMX > theophylline. The antagonism by these xanthines was shown to be competitive, the pA2 value for 8-PT being 7.16. In concentrations slightly higher than those used to test its ability to antagonize the adenosine receptor, IBMX and 8-PT increased the amplitude of e.p.ps without modifying their decay phase or the resting membrane potential of the muscle fibre. 4 The adenosine uptake inhibitor, nitrobenzylthioinosine (NBI) and the adenosine deaminase inhibitor, erythro-9(2-hydroxy-3-nonyl)adenine (EHNA), in concentrations virtually devoid of effect on neuromuscular transmission, potentiated the inhibitory effect of adenosine at the rat diaphragm neuromuscular junction. The potentiation factors were about 2.6 for NBI (51M), 2.2 for EHNA (25 pM) and 4.6 for the combination of NBI (5 FM) and EHNA (25 FM). 5 It is concluded that both uptake and deamination contribute to the inactivation of adenosine at the rat diaphragm neuromuscular junction and that in this preparation the inhibitory effect of adenosine on transmission is mediated by a xanthine-sensitive adenosine receptor with an agonist profile which does not fit the criteria for its classification either as an A, or A2-adenosine receptor.

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“…However, application of the phosphodiesterase inhibitor Ro20-1724 to the frog NMJ enhanced mepp frequency, an action similar to that of theophylline. Silinsky (1984) and Silinsky and Vogel (1987) have also reported that Ro20-1724 and other phosphodiesterase inhibitors increase mepp frequency. Thus, theophylline, at 100 PM and 1 mM, may increase spontaneous transmitter release in part by phosphodiesterase inhibition and enhancement of intraterminal cyclic AMP levels.…”

Section: Stimulatory Effects Of Theophyllinementioning

confidence: 96%

“…7). Silinsky (1984) and Silinsky and Vogel (1987) have also reported that Ro20-1724 increases mepp frequency and reduces the size of the endplate current.…”

Section: Effects Of Adenosine Deaminasementioning

confidence: 96%

Dual effects of theophylline on spontaneous transmitter release from frog motor nerve terminals

Barry

1988

J. Neurosci.

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Alkylxanthine drugs, such as theophylline, block adenosine receptors, inhibit phosphodiesterases and other enzymes, and cause the release of calcium from intracellular stores. Adenosine receptor blockade occurs at low micromolar concentrations of the drugs, while other effects occur in the millimolar concentration range. The effects of theophylline were tested on spontaneous transmitter release at the frog cutaneous-pectoris neuromuscular junction (NMJ). A change in the frequency, but not the amplitude, of miniature endplate potentials (mepps) was interpreted as a change in spontaneous transmitter release. In normal Ringer's, theophylline, at concentrations of 100 microM and 1 mM, theophylline had no consistent effect on spontaneous release. In contrast, theophylline produced dual effects on mepp frequency in hyperosmotic Ringer's. At 10 microM, theophylline depressed mepp frequency, while, at 100 microM and 1 mM, theophylline increased mepp rate. Since low micromolar concentrations of theophylline depressed spontaneous transmitter release, this action may result from adenosine receptor blockade and inhibition of a tonic, stimulatory effect of adenosine. This hypothesis was supported by the following experimental results: (1) Micromolar concentrations of theophylline reversed the effects of applied adenosine on neuromuscular transmission. (2) The inhibitory effect of theophylline was mimicked by 2 other alkylxanthines, 8-phenyltheophylline and 8-p-sulfophenyltheophylline. These drugs may be more specific adenosine receptor antagonists than theophylline. (3) The inhibitory effect of theophylline was mimicked by adenosine deaminase, an enzyme that breaks down and inactivates adenosine. (4) The depressant action of theophylline was masked by the addition of adenosine deaminase to the hyperosmotic Ringer's. Application of adenosine to the frog NMJ reduces spontaneous transmitter output.(ABSTRACT TRUNCATED AT 250 WORDS)

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Independent control of channel closure and block of open channels by methylxanthines at acetylcholine receptors in frog.

Cited by 9 publications

References 23 publications

The role of cyclic AMP and its protein kinase in mediating acetylcholine release and the action of adenosine at frog motor nerve endings

The role of cyclic AMP and its protein kinase in mediating acetylcholine release and the action of adenosine at frog motor nerve endings

On the adenosine receptor and adenosine inactivation at the rat diaphragm neuromuscular junction

Dual effects of theophylline on spontaneous transmitter release from frog motor nerve terminals

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