Calcium-independent inhibition of GABA(A) current by caffeine in hippocampal slices.
Although inhibitory postsynaptic currents (IPSCs) mediated by GABA(A) receptor is thought to be affected by intracellular calcium ion concentration ([Ca2+]i), origin or route of [Ca2+]i increment has not been well elucidated. Reports on the effect of [Ca2+]i elevation on GABA(A)ergic IPSCs per se are also controversial. In this study, effects of caffeine and several other [Ca2+]i-mobilizing drugs were examined on the IPSCs in acute slices of rat hippocampus. Using the patch clamp recording method, spontaneous and evoked currents were recorded from CA3 neurons. Caffeine strongly inhibited both extra-synaptic and synaptic GABAergic IPSCs, regardless of the presence or absence of extracellular Ca2+. This inhibition was not relieved by the intracellular application of EGTA or 1,2-bis(2-aminophenoxy)-ethane-N,N,N',N'-tetraacetic acid (BAPTA). This inhibition by caffeine was not prevented by preequilibration with caffeine. Ca2+ store depletion caused by thapsigargin or repetitive stimulation by caffeine could not prevent the inhibition. Moreover, ruthenium red and ryanodine could not overcome the inhibition. On the contrary, GABA(A)ergic currents were not inhibited by stimulation with several Ca2+-mobilizing agonists. Forskolin could not mimic the effect of caffeine on the IPSC, and caffeine inhibited the IPSC in the presence of adenosine. These results suggest that intracellular Ca2+ mobilization through ryanodine-sensitive store stimulation does not significantly affect GABAergic IPSCs, and most of the inhibitory effect of caffeine is independent of [Ca2+]i elevation under the present experimental conditions.
Taketo
M
M
Department of Physiology 1, Faculty of Medicine, Kansai Medical University, 10-15 Fumizono-cho Moriguchi, Osaka 570-8506, Japan. taketom@takii.kmu.ac.jp
Matsuda
H
H
Yoshioka
T
T
D000109:Acetylcholine / Q000494:pharmacology; D000255:Adenosine Triphosphate / Q000494:pharmacology; D000818:Animals; D000831:Animals, Newborn; D001920:Bradykinin / Q000494:pharmacology; D002110:Caffeine / Q000494:pharmacology*; D002118:Calcium / Q000378:metabolism*; D000697:Central Nervous System Stimulants / Q000494:pharmacology; D004347:Drug Interactions; D004558:Electric Stimulation / Q000379:methods; D004791:Enzyme Inhibitors / Q000494:pharmacology; D018755:GABA Agonists / Q000494:pharmacology; D006624:Hippocampus / Q000187:drug effects* / Q000502:physiology; D066298:In Vitro Techniques; D007539:Isonicotinic Acids / Q000494:pharmacology; D008564:Membrane Potentials / Q000187:drug effects / Q000528:radiation effects; D009433:Neural Inhibition / Q000187:drug effects; D018408:Patch-Clamp Techniques / Q000379:methods; D051381:Rats; D017208:Rats, Wistar; D011963:Receptors, GABA-A / Q000502:physiology*; D012430:Ruthenium Red / Q000494:pharmacology; D012433:Ryanodine / Q000494:pharmacology; D019284:Thapsigargin / Q000494:pharmacology
D000697:Central Nervous System Stimulants; D004791:Enzyme Inhibitors; D018755:GABA Agonists; D007539:Isonicotinic Acids; D011963:Receptors, GABA-A; D012430:Ruthenium Red; D012433:Ryanodine; D002110:Caffeine; D019284:Thapsigargin; D000255:Adenosine Triphosphate; D000109:Acetylcholine; D001920:Bradykinin; D002118:Calcium; C015300:isoguvacine