Modulation of Ca2+ channel currents by a novel antidementia drug N-(4-Acetyl-1-piperazinyl)-p-fluorobenzamide monohydrate (FK960) in rat hippocampal neurons.
N-(4-Acetyl-1-piperazinyl)-p-fluorobenzamide monohydrate (FK960), a novel antidementia drug, has been demonstrated to ameliorate memory deficits in various experimental models of dementia. This drug selectively increases somatostatin release from hippocampal slices and augments long-term potentiation (LTP) in the CA3 area of the hippocampus. In the present study, the effects of FK960 on voltage-activated Ca2+ channels were investigated in acutely isolated rat hippocampal neurons, using whole-cell patch-clamp technique to clarify the cellular mode of action of FK960. Application of somatostatin significantly reduced Ca2+ currents via G protein-coupled signaling pathways. This inhibitory effect was significantly abolished by FK960 when applied in combination. In contrast, FK960 showed only modest inhibition on the reduction in Ca2+ currents produced by baclofen, an agonist of GABAB receptor. Intracellular application of the protein kinase inhibitor H-7 did not alter somatostatin-induced inhibition and had no significant effect on blockade by FK960. In addition, application of FK960 alone produced modest but apparent increases in Ca2+ currents without significant changes in the activation kinetics of the channels. The dose-response relationship on calcium current enhancement was bell-shaped with a maximum effect at 0.1 microM FK960, the same concentration as that for increasing on somatostatin release and CA3-LTP. These results show that FK960 reverses G protein-dependent inhibition of Ca2+ currents by somatostatin in hippocampal neurons. Enhancement of Ca2+ currents by FK960 may be due to its modulatory actions on Ca2+ channels, rather than removal of G protein-inhibited tonic currents. Together, these mechanisms may be involved in the selective effects of FK960 on somatostatin release, excitatory transmission, and synaptic plasticity in the hippocampus.
Wang
Feng
F
Medicinal Biology Research Laboratories, Fujisawa Pharmaceutical Co. Ltd., Kashima, Osaka 532-8514, Japan.
Matsuoka
Nobuya
N
Mutoh
Seitaro
S
Kaneko
Shuji
S
D000818:Animals; D001549:Benzamides / Q000494:pharmacology*; D015220:Calcium Channels / Q000502:physiology*; D004347:Drug Interactions; D004789:Enzyme Activation; D019204:GTP-Binding Proteins / Q000378:metabolism; D006624:Hippocampus / Q000166:cytology*; D017774:Long-Term Potentiation / Q000187:drug effects; D008297:Male; D009474:Neurons / Q000187:drug effects* / Q000502:physiology; D010879:Piperazines / Q000494:pharmacology*; D011494:Protein Kinases / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D013004:Somatostatin / Q000494:pharmacology
D001549:Benzamides; D015220:Calcium Channels; C102991:N-(4-acetyl-1-piperazinyl) -4-fluorobenzamide monohydrate; D010879:Piperazines; D013004:Somatostatin; D011494:Protein Kinases; D019204:GTP-Binding Proteins