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 responses of slice-cultured Purkinje cells to trans-DL-1-amino-1,3-cyclopentanedicarboxylic acid (t-ACPD) were examined by intracellular recording techniques and fura-2 microfluorometry. Bath-application of t-ACPD (100 microM, 30 s), a selective agonist of metabotropic glutamate receptors (mGluRs), to Purkinje cells voltage-clamped near their resting potential -65 to -60 mV) consistently induced a transient inward current, followed by a slower outward current (Iout). This outward current was characterized by a linear current-voltage relationship in the range from -130 to -60 mV and accompanied by a significant decrease in membrane conductance. The extrapolated reversal potential of Iout was positive to 0 mV. When t-ACPD was applied for 60 s or more it became apparent that Iout emerged in parallel to the wash-out of t-ACPD. Microfluorometric fura-2 measurements in combination with electrophysiological recordings were used to assess the relation between Iout and intracellular free calcium concentration ([Ca2+]i). In contrast to the inward current that was associated with a transient elevation in [Ca2+]i. Iout was not correlated with an elevated [Ca2+]i. When t-ACPD was applied in the presence of caffeine (5 mM), Iout was reversibly enhanced in amplitude. Caffeine affected neither the t-ACPD-induced calcium signal nor the resting [Ca2+]i. While longer applications of caffeine alone induced outward currents with a current-voltage relationship similar to that of Iout, short applications (30 s) of caffeine had no detectable effect per se but still were effective in enhancing Iout when applied in conjunction with t-ACPD. 3-Isobutyl-1-methylxanthine (IBMX, 0.5 mM), a more selective and potent phosphodiesterase inhibitor than caffeine, exhibited caffeine-like effects at a 10-fold lower concentration. We propose that Iout is generated by a transient inhibition of an inward current that is tonically active at rest and largely voltage-independent in the range tested. Our observations provide evidence for an involvement of cyclic nucleotide second messenger systems in the regulation of this current.
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PMID:Activation of metabotropic glutamate receptors induces an outward current which is potentiated by methylxanthines in rat cerebellar Purkinje cells. 768 80

The neuronal dipeptide N-acetylaspartylglutamate (NAAG) fulfills several of the criteria for classification as a neurotransmitter including localization in synaptic vesicles, calcium-dependent release after neuronal depolarization, and low potency activation of N-methyl-D-aspartate receptors. In the present study, the influence of NAAG on metabotropic receptor activation in cerebellar granule cells was examined in cell culture. Stimulation of granule cell adenylate cyclase with forskolin increased cyclic AMP (cAMP) several hundredfold above basal levels within 10 min in a concentration-dependent manner. Although glutamate, NAAG, and the metabotropic receptor agonist trans-1-amino-1,3-cyclopentanedicarboxylic acid did not alter the low basal cAMP levels, the application of 300 microM glutamate or NAAG or trans-1-amino-1,3-cyclopentanedicarboxylic acid reduced forskolin-stimulated cAMP in granule cells by 30-50% in the absence or presence of inhibitors of ionotropic acidic amino acid receptors, as well as 2-amino-4-phosphonobutyrate. No additivity in the inhibition of cAMP was found when 300 microM NAAG and trans-1-amino-1,3-cyclopentanedicarboxylic acid were coapplied. The beta-analogue of NAAG failed to reduce cAMP levels. Similar effects of NAAG and glutamate were obtained under conditions of inhibition of phosphodiesterase activity and were prevented by pretreatment of the cells with pertussis toxin. These data are consistent with the activation by NAAG of a metabotropic acidic amino acid receptor coupled to an inhibitory G protein. In contrast, the metabotropic acidic amino acid receptor coupled to phosphoinositol turnover in these cells was not activated by NAAG.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:N-acetylaspartylglutamate inhibits forskolin-stimulated cyclic AMP levels via a metabotropic glutamate receptor in cultured cerebellar granule cells. 768 44