Stochastic amplification of calcium-activated potassium currents in Ca2+ microdomains
Small conductance (SK) calcium-activated potassium channels are found in many tissues throughout the body and open in response to elevations in intracellular calcium. In hippocampal neurons, SK channels are spatially co-localized with L-Type calcium channels. Due to the restriction of calcium transients into microdomains, only a limited number of L-Type Ca2+ channels can activate SK and, thus, stochastic gating becomes relevant. Using a stochastic model with calcium microdomains, we predict that intracellular Ca2+ fluctuations resulting from Ca2+ channel gating can increase SK2 subthreshold activity by 1–2 orders of magnitude. This effectively reduces the value of the Hill coefficient. To explain the underlying mechanism, we show how short, high-amplitude calcium pulses associated with stochastic gating of calcium channels are much more effective at activating SK2 channels than the steady calcium signal produced by a deterministic simulation. This stochastic amplification results from two factors: first, a supralinear rise in the SK2 channel’s steady-state activation curve at low calcium levels and, second, a momentary reduction in the channel’s time constant during the calcium pulse, causing the channel to approach its steady-state activation value much faster than it decays. Stochastic amplification can potentially explain subthreshold SK2 activation in unified models of both sub- and suprathreshold regimes. Furthermore, we expect it to be a general phenomenon relevant to many proteins that are activated nonlinearly by stochastic ligand release.
KeywordsStochastic Calcium-activated potassium SK2 Microdomain Noise Hill coefficient Subthreshold
The authors wish to thank Dr. Berj Bardakjian, Dr. Avrama Blackwell, Behnam Kia, Ernest Ho, and Pengpeng Cao for valuable discussion. We are grateful to Dr. Neil V. Marrion and Dr. Pankaj Sah for providing elaboration on their published experimental results, which were essential for this paper. We also thank Janet Stanley for proofreading the manuscript and Kerstin Menne for making her GENESIS code available. The authors also wish to acknowledge ONR and NSERC for providing funding for this work.
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