Stochastic amplification of calcium-activated potassium currents in Ca2+ microdomains
- 284 Downloads
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.
- Bowden, S., Fletcher, S., Loane, D., & Marrion, N. (2001). Somatic colocalization of rat SK1 and D class (Cav 1.2) L-type calcium channels in rat CA1 hippocampal pyramidal neurons. Journal of Neuroscience, 21(20), 175.Google Scholar
- Bower, J., Beeman, D., & Hucka, M. (2002). The GENESIS simulation system. In M. A. Arbib (Ed.), The handbook of brain theory and neural networks (pp. 475–478, 2nd ed.). Cambridge: MIT Press.Google Scholar
- Bower, J., Beeman, D., & Wylde, A. (1998). The book of GENESIS: Exploring realistic neural models with the GEneral NEural SImulation System (2nd ed.). New York: Springer.Google Scholar
- Catterall, W., Perez-Reyes, E., Snutch, T., & Striessnig, J. (2010). Voltage-gated calcium channels: Cav1.3. Last modified on 2010-07-01. Accessed on 13 October 2010. IUPHAR database (IUPHAR-DB) URL http://www.iuphar-db.org/DATABASE/ObjectDisplayForward?objectId=530.
- Choi, S., Yu, E., Kim, D., Urbano, F., Makarenko, V., Shin, H., et al. (2010). Subthreshold membrane potential oscillations in inferior olive neurons are dynamically regulated by P/Q-and T-type calcium channels: A study in mutant mice. The Journal of Physiology, 588(16), 3031.PubMedCrossRefGoogle Scholar
- De Schutter, E,, & Smolen, P. (1998). Calcium dynamics in large neuronal models. In C. Koch, & I. Segev (Eds.), Methods in neuronal modeling: From ions to networks (pp. 211-215, 2nd ed., chap. 6). Cambridge: MIT Press.Google Scholar
- Dyhrfjeld-Johnsen, J., Maier, J., Schubert, D., Staiger, J., Luhmann, H., Stephan, K., et al. (2005). CoCoDat: A database system for organizing and selecting quantitative data on single neurons and neuronal microcircuitry. Journal of Neuroscience Methods, 141(2), 291–308.PubMedCrossRefGoogle Scholar
- Eliasmith, C., & Anderson, C. (2004). Neural engineering: Computation, representation, and dynamics in neurobiological systems. Cambridge: MIT Press.Google Scholar
- Hallworth, N., Wilson, C., & Bevan, M. (2003). Apamin-sensitive small conductance calcium-activated potassium channels, through their selective coupling to voltage-gated calcium channels, are critical determinants of the precision, pace, and pattern of action potential generation in rat subthalamic nucleus neurons in vitro. Journal of Neuroscience, 23(20), 7525.PubMedGoogle Scholar
- Hille, B. (2001). Ion channels of excitable membranes (3rd ed.). Sinauer Sunderland, MA.Google Scholar
- Jacobson, D., Mendez, F., Thompson, M., Torres, J., Cochet, O., & Philipson, L. (2010). Calcium-activated and voltage-gated potassium channels of the pancreatic islet impart distinct and complementary roles during secretagogue induced electrical responses. The Journal of Physiology, 588(18), 3525–3537.PubMedCrossRefGoogle Scholar
- Knopfel, T., Vranesic, I., Gahwiler, B., & Brown, D. (1990). Muscarinic and beta-adrenergic depression of the slow Ca2+-activated potassium conductance in hippocampal CA3 pyramidal cells is not mediated by a reduction of depolarization-induced cytosolic Ca2+ transients. Proceedings of the National Academy of Science, 87, 4083–4087.CrossRefGoogle Scholar
- Mainen, Z., & Sejnowski, T. (1998). Modeling active dendritic processes in pyramidal neurons. In C. Koch, & I. Segev (Eds.), Methods in neuronal modeling: From ions to networks (pp. 171-210). Cambridge: MIT Press.Google Scholar
- Marder, E., Kopell, N., & Karen, S. (1999). How computation aids in understanding biological networks. In P. S. G. Stein, S. Grillner, A.I. Selverston, & D. G. Stuart (Eds.), Neurons, networks, and motor behavior (pp. 139-150, chap. 13). Cambridge: MIT Press.Google Scholar
- Millership, J., Heard, C., Fearon, I., & Bruce, J. (2010). Differential regulation of calcium-activated potassium channels by dynamic intracellular calcium signals. Journal of Membrane Biology, 235(3), 191–210.Google Scholar
- Navedo, M., Amberg, G., Westenbroek, R., Sinnegger-Brauns, M., Catterall, W., Striessnig, J., et al. (2007). Cav1.3 channels produce persistent calcium sparklets, but Cav1.2 channels are responsible for sparklets in mouse arterial smooth muscle. American Journal of Physiology—Heart and Circulatory Physiology, 293(3), H1359.CrossRefGoogle Scholar
- Sherman, A. (1996). Contributions of modeling to understanding stimulus-secretion coupling in pancreatic beta-cells. American Journal of Physiology—Endocrinology and Metabolism, 271(2), E362.Google Scholar