Small-Conductance Ca2+-Dependent K+ Channels Are the Target of Spike-Induced Ca2+ Release in a Feedback Regulation of Pyramidal Cell Excitability

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Abstract
Cooperative regulation of inosiol-1,4,5-trisphosphate receptors (IP3Rs) by Ca2+ and IP3 has been increasingly recognized, although its functional significance is not clear. The present experiments first confirmed that depolarization-induced Ca2+ influx triggers an outward current in visual cortex pyramidal cells in normal medium, which was mediated by apamin-sensitive, small-conductance Ca2+-dependent K+ channels (SK channels). With IP3-mobilizing neurotransmitters bath-applied, a delayed outward current was evoked in addition to the initial outward current and was mediated again by SK channels. Calcium turnover underlying this biphasic SK channel activation was investigated. By voltage-clamp recording, Ca2+ influx through voltage-dependent Ca2+ channels (VDCCs) was shown to be responsible for activating the initial SK current, whereas the IP3R blocker heparin abolished the delayed component. High-speed Ca2+ imaging revealed that a biphasic Ca2+ elevation indeed underlays this dual activation of SK channels. The first Ca2+ elevation originated from VDCCs, whereas the delayed phase was attributed to calcium release from IP3Rs. Such enhanced SK currents, activated dually by incoming and released calcium, were shown to intensify spike-frequency adaptation. We propose that spike-induced calcium release from IP3Rs leads to SK channel activation, thereby fine tuning membrane excitability in central neurons.