title: A distinct form of calcium release down-regulates membrane excitability in neocortical pyramidal cells.
abstract: We reported a novel type of calcium release from inositol-1,4,5-trisphosphate (IP(3))-sensitive calcium stores synergistically induced by muscarinic acetylcholine receptor (mAchR)-mediated increase in IP(3) and action potential-induced calcium influx (IP(3)-assisted calcium-induced calcium release, IP(3)-assisted CICR). To clarify its functional significance, the effects of IP(3)-assisted CICR on spike-frequency adaptation were examined in layer II/III neurons from rat visual cortex slices. IP(3)-assisted CICR was enabled with a high concentration of the mAchR agonist carbachol (10 microM). The magnitude of this CICR was the more augmented at higher firing frequencies. With 10 microM carbachol, spike-frequency adaptation was reduced for spike trains at 'low' firing frequencies (6-10 Hz), but was rather enhanced at 'high' firing rates (16-22 Hz): excitability was down-regulated at 'high' frequencies. With 1 microM carbachol, by contrast, IP(3)-assisted CICR failed to occur, and spike-frequency adaptation was always reduced at any spike frequencies. Intracellular injection of the IP(3) receptor blocker heparin prevented both the mAchR-mediated occurrence of IP(3)-assisted CICR and enhancement of spike-frequency adaptation with 10 microM carbachol. Both of these mAchR-mediated effects were reproduced by intracellular IP(3) injection, and were shown to be associated with each other by simultaneous recordings of membrane potential and intracellular calcium increase. We propose that IP(3)-assisted CICR offers a novel way to protect these cortical neurons from hyperexcitability and presumably from excitotoxic cell death.
authors.affiliation: Department of Integrative Brain Science, Kyoto University Graduate School of Medicine, Japan.
authors.forename: K
authors.initials: K
authors.lastname: Yamamoto
authors.forename: K
authors.initials: K
authors.lastname: Hashimoto
authors.forename: M
authors.initials: M
authors.lastname: Nakano
authors.forename: S
authors.initials: S
authors.lastname: Shimohama
authors.forename: N
authors.initials: N
authors.lastname: Kato
mesh_terms: D000200:Action Potentials / Q000187:drug effects / Q000502:physiology*; D000818:Animals; D002118:Calcium / Q000378:metabolism*; D015220:Calcium Channels / Q000378:metabolism; D020013:Calcium Signaling / Q000187:drug effects / Q000502:physiology; D002217:Carbachol / Q000494:pharmacology; D002462:Cell Membrane / Q000187:drug effects / Q000378:metabolism*; D002614:Chelating Agents / Q000494:pharmacology; D015536:Down-Regulation / Q000187:drug effects / Q000502:physiology*; D004558:Electric Stimulation; D016257:Fura-2; D015544:Inositol 1,4,5-Trisphosphate / Q000378:metabolism* / Q000494:pharmacology; D053496:Inositol 1,4,5-Trisphosphate Receptors; D018721:Muscarinic Agonists / Q000494:pharmacology; D017966:Pyramidal Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D051381:Rats; D017208:Rats, Wistar; D018160:Receptors, Cytoplasmic and Nuclear / Q000819:agonists / Q000378:metabolism; D011976:Receptors, Muscarinic / Q000187:drug effects / Q000378:metabolism; D014793:Visual Cortex / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*
chemical_list: D015220:Calcium Channels; D002614:Chelating Agents; D053496:Inositol 1,4,5-Trisphosphate Receptors; D018721:Muscarinic Agonists; D018160:Receptors, Cytoplasmic and Nuclear; D011976:Receptors, Muscarinic; D015544:Inositol 1,4,5-Trisphosphate; D002217:Carbachol; D002118:Calcium; D016257:Fura-2