8-[2-(2-pentyl-cyclopropylmethyl)-cyclopropyl]-octanoic acid stimulates GABA release from interneurons projecting to CA1 pyramidal neurons in the rat hippocampus via pre-synaptic alpha7 acetylcholine receptors.
Nicotinic acetylcholine (ACh) receptors, such as alpha7, alpha3beta4 and alpha4beta2 receptors in the hippocampus, are suggested to modulate neurotransmitter release. 8-[2-(2-Pentyl-cyclopropylmethyl)-cyclopropyl]-octanoic acid (DCP-LA) (100 nM), a linoleic acid derivative, potentiated responses of alpha7, alpha3beta4 and alpha4beta2 ACh receptors expressed in Xenopus oocytes that are blocked by 3-(1-[dimethylaminopropyl] indol-3-yl)-4-[indol-3-yl] maleimide (GF109203X), a selective inhibitor of protein kinase C (PKC), except for alpha3beta4 ACh receptors. DCP-LA enhanced the nicotine-triggered release of GABA from rat hippocampal slices in the presence of tetrodotoxin in a bell-shaped dose-dependent manner at concentrations ranging from 10 nM to 10 microM, although DCP-LA by itself had no effect on GABA release. The DCP-LA action was inhibited by GF109203X or alpha-bungarotoxin, an inhibitor of alpha7 ACh receptors, but not by mecamylamine or dihydro-beta-erithroidine, an inhibitor of alpha3beta4 and alpha4beta2 ACh receptors. A similar effect on GABA release was obtained with 12-O-tetradecanoylphorbol 13-acetate, a PKC activator. DCP-LA (100 nM) also enhanced GABA release triggered by choline, an agonist of alpha7 ACh receptors, but not 3-[2(s)-azetidinylmethoxy] pyridine, an agonist of alpha4beta2 ACh receptors. In addition, DCP-LA (100 nM) increased the rate of nicotine-triggered GABA(A) receptor-mediated miniature inhibitory post-synaptic currents, monitored from CA1 pyramidal neurons of rat hippocampal slices, and the effect was also inhibited by GF109203X or alpha-bungarotoxin but not by mecamylamine. Thus, the results of the present study indicate that DCP-LA stimulates GABA release by enhancing activity of pre-synaptic alpha7 ACh receptors present on the GABAergic terminals of interneurons that transmit to CA1 pyramidal neurons via a PKC pathway.
Kanno
Takeshi
T
Department of Physiology, Hyogo College of Medicine, Nishinomiya, Japan.
Yaguchi
Takahiro
T
Yamamoto
Satoshi
S
Yamamoto
Hideyuki
H
Fujikawa
Hirokazu
H
Nagata
Tetsu
T
Tanaka
Akito
A
Nishizaki
Tomoyuki
T
D000818:Animals; D002210:Caprylates / Q000494:pharmacology*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006624:Hippocampus / Q000166:cytology / Q000187:drug effects* / Q000502:physiology; D007211:Indoles / Q000494:pharmacology; D007395:Interneurons / Q000166:cytology* / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D008301:Maleimides / Q000494:pharmacology; D008564:Membrane Potentials / Q000187:drug effects; D009434:Neural Pathways; D009865:Oocytes / Q000502:physiology; D009924:Organ Culture Techniques; D018408:Patch-Clamp Techniques; D017729:Presynaptic Terminals / Q000378:metabolism; D011493:Protein Kinase C / Q000378:metabolism; D017966:Pyramidal Cells / Q000166:cytology*; D051381:Rats; D017208:Rats, Wistar; D011978:Receptors, Nicotinic / Q000378:metabolism*; D014981:Xenopus; D064569:alpha7 Nicotinic Acetylcholine Receptor; D005680:gamma-Aminobutyric Acid / Q000378:metabolism*
C506022:8-(2-(2-pentyl-cyclopropylmethyl)cyclopropyl)octanoic acid; D002210:Caprylates; C579165:Chrna7 protein, rat; D004791:Enzyme Inhibitors; D007211:Indoles; D008301:Maleimides; D011978:Receptors, Nicotinic; C427403:alpha(4)beta(4) nicotinic receptor; D064569:alpha7 Nicotinic Acetylcholine Receptor; C403530:nicotinic receptor alpha3beta4; D005680:gamma-Aminobutyric Acid; D011493:Protein Kinase C; C070515:bisindolylmaleimide I