LY 294002 inhibits adenosine receptor activation by a mechanism independent of effects on PI-3 kinase or casein kinase II |
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Authors: | T?J?Searl Email author" target="_blank">E?M?SilinskyEmail author |
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Institution: | (1) Department of MolecularPharmacology and Biological Chemistry (MPBC), Northwestern University Medical School, Chicago, Illinois, USA;(2) Department of Molecular Pharmacology and Biological Chemistry (MPBC), Northwestern University Medical School, 303 East Chicago Avenue, Chicago, IL 60611, USA |
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Abstract: | Adenosine reduces both evoked and spontaneous calcium-dependent acetylcholine (ACh) release through a mechanism downstream
of calcium entry at amphibian motor nerve endings (Silinsky EM. J Physiol 1984; 346: 243–56). LY 294002 (2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one),
an inhibitor of both phosphoinositide-3 kinase (PI-3 kinase) and casein kinase II, has been reported to increase spontaneous
ACh release reflected in miniature endplate potential (MEPP) frequencies independently of intraterminal calcium at the frog
neuromuscular junction (Rizzoli SO, Betz WJ. J Neurosci 2002; 22: 10680–9). It has been suggested that the increase in MEPP
frequency caused by LY 294002, is mediated through an action on synaptotagmins, vesicle associated calcium sensors believed
to trigger synaptic vesicle exocytosis. We thus examined the effects of adenosine on MEPP frequencies and evoked ACh release
reflected as endplate potentials (EPPs) in order to determine if the presumed calcium-independent ACh release is affected
by adenosine. We also wanted to determine if PI-3 kinase or casein kinase II is involved in mediating or modulating the inhibitory
effects of adenosine. To these ends, we examined the effects of adenosine in the presence of LY 294002, wortmannin (a highly
selective the PI-3 kinase inhibitor), or DRB (5,6-dichlorobenzimidazole riboside, an inhibitor of casein kinase II). LY 294002
reduced the sensitivity of both MEPP frequencies and the nerve-evoked calcium dependent EPPs to adenosine. The occlusive effects
of LY 294002 on the actions of adenosine on MEPPs and EPPs were overcome by increasing adenosine concentration. Neither wortmannin
nor DRB had any effect on the sensitivity of the EPPs to adenosine indicating that neither PI-3 kinase nor casein kinase II
inhibition mediates the reduction in motor-nerve terminal sensitivity to adenosine produced by LY 294002. The results indicate
a competitive relationship between LY 294002 and adenosine at A1 receptors at the frog neuromuscular junction. This effect is independent of the previously described effects of LY 294002
on the exocytotic process, and is also independent of PI-3 kinase or casein kinase II. |
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Keywords: | acetylcholine adenosine casein kinase neuromuscular junction neurotransmitter release PI-3 kinase |
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