- 1Potentiation of calcium-activated non-selective cation (CAN) channels was studied in rat hippocampal neurones. CAN channels were activated by IP3-dependent Ca2+ release following metabotropic glutamate receptor (mGluR) stimulation either by Schaffer collateral input to CA1 neurones in brain slices in which ionotropic glutamate and GABAA receptors, K+ channels, and the Na+-Ca2+ exchanger were blocked or by application of the mGluR antagonist ACPD in cultured hippocampal neurones.
- 2The CAN channel-dependent depolarization (ΔVCAN) was potentiated when [Ca2+]i was increased in neurones impaled with Ca2+-containing microelectrodes.
- 3Fura-2 measurements revealed a biphasic increase in [Ca2+]i when 200 μm ACPD was bath applied to cultured hippocampal neurones. This increase was greatly attenuated in the presence of Cd2+.
- 4Thapsigargin (1 μm) caused marked potentiation of ΔVCAN in CA1 neurones in the slices and of the CAN current (ICAN) measured in whole cell-clamped cultured hippocampal neurones.
- 5Ryanodine (20 μm) also led to a potentiation of ΔVCAN while neurones pretreated with 100 μm dantrolene failed to show potentiation of ΔVCAN when impaled with Ca2+-containing microelectrodes.
- 6The mitochondrial oxidative phosphorylation uncoupler carbonyl cyanide m-chlorophenyl hydrazone (2 μm) also caused a potentiation of ΔVCAN.
- 7CAN channels are subject to considerable potentiation following an increase in [Ca2+]i due to Ca2+ release from IP3-sensitive, Ca2+-sensitive, or mitochondrial Ca2+ stores. This ICAN potentiation may play a crucial role in the ‘amplification’ phase of excitotoxicity.