Analogs of cyclic AMP decrease gamma-aminobutyric acidA receptor-mediated chloride current in cultured rat hippocampal neurons via an extracellular site.
We have studied the effects of the membrane-permeant cyclic AMP analogs 8-bromo-cyclic AMP and 8-(4-chlorophenylthio)-cyclic AMP (CPT-cAMP) on the gamma-aminobutyric acidA (GABAA) receptor-mediated chloride current in cultured rat hippocampal neurons. External perfusion with 8-bromo-cyclic AMP or CPT-cAMP caused a reversible, concentration-dependent decrease in the response to GABA. Adding the protein kinase inhibitor H-8 to the perfusing medium or the intracellular recording solution did not affect the response to GABA, which was decreased by CPT-cAMP as before. L858051, a water-soluble derivative of the adenylate cyclase activator forskolin, did not decrease the response to GABA even in the presence of the phosphodiesterase inhibitor 3-isobutylmethylxanthine. External cyclic AMP also caused a reversible, concentration-dependent decrease in the response to GABA with a potency similar to that of 8-Br-cAMP. When cAMP was present in the intracellular recording solution cAMP and CPT-cAMP decreased the response to GABA as before. These experiments suggest that analogs of cAMP decrease GABAA receptor-activated chloride current by acting at an extracellular site.
Laboratory of Neurophysiology, National Institute for Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland.
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Lambert
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Harrison
D015056:1-Methyl-3-isobutylxanthine / Q000494:pharmacology; D000262:Adenylyl Cyclases / Q000502:physiology; D000818:Animals; D002478:Cells, Cultured; D018118:Chloride Channels; D000242:Cyclic AMP / Q000031:analogs & derivatives / Q000494:pharmacology*; D005110:Extracellular Space / Q000187:drug effects; D006624:Hippocampus / Q000187:drug effects* / Q000378:metabolism; D007546:Isoquinolines / Q000494:pharmacology; D008565:Membrane Proteins / Q000187:drug effects*; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism; D011494:Protein Kinases / Q000502:physiology; D051381:Rats; D011963:Receptors, GABA-A / Q000187:drug effects* / Q000502:physiology
D018118:Chloride Channels; D007546:Isoquinolines; D008565:Membrane Proteins; D011963:Receptors, GABA-A; C053177:N-(2-(methylamino)ethyl)-5-isoquinolinesulfonamide; D000242:Cyclic AMP; D011494:Protein Kinases; D000262:Adenylyl Cyclases; D015056:1-Methyl-3-isobutylxanthine