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The Dynamics of Intracellular Ca2+ Signals

The Dynamics of Intracellular Ca2+ Signals. Jianwei Shuai ( 帅建伟 ) Department of Physics Xiamen University. Outline. Introduction IP3R Ca 2+ channel model Ca 2+ blips with single IP 3 R Ca 2+ channel Ca 2+ puffs with clustered Ca 2+ channels Ca 2+ waves at the global cell level

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The Dynamics of Intracellular Ca2+ Signals

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  1. The Dynamics of Intracellular Ca2+ Signals Jianwei Shuai (帅建伟) Department of Physics Xiamen University

  2. Outline • Introduction • IP3R Ca2+ channel model • Ca2+ blips with single IP3R Ca2+ channel • Ca2+ puffs with clustered Ca2+ channels • Ca2+ waves at the global cell level • Summary

  3. Fixed Ca2+ via Moving Ca2+

  4. Moving Calcium Ions A life and death signal in cells Life beginning Sperm Ca2+ Oscillation Cell Division Egg Life ending High Calcium Concentration protein-digesting enzymes Cell Death • In-between: • Brain memory • Ca2+-related diseases: Cancer, Alzheimer’s • Communication between cells, • Communication among different organelles within a cell

  5. Cell Structure

  6. Ca2+ Release Dynamics IP3 Cytosol [Ca]Local>10mM Pump IP3R Cell Membrane ER Pump

  7. Ca2+-induced Ca2+ release propagates Ca2+ waves Cytosol Membrane ER Low [Ca] opens the IP3R channels: fast binding; High [Ca] inhibits the IP3R channels: slow binding.

  8. How does Ca2+ act as a cellular signal? Ca2+ concepts Ca2+ Concentration Ca2+ Oscillation Spatiotemporal Ca2+ wave Cellular information is encoded by the spatiotemporal Ca2+ patterns (e.g. frequency and amplitude of oscillation). Ca2+ Signal

  9. Green light Calcium Fluorescence dye Blue light Blue light Blue light Technique to Visualize Cytosolic Ca2+

  10. Ca2+ spreading wave Ian Parker, UC Irvine

  11. Ca2+ spiral wave Lechleiter, Girard, Peralta and Clapham, Science, 1991

  12. Fine structure underlying Ca2+ waves Marchant & Parker, EMBO J. 1999

  13. Ca2+ waves consist of puffs puff Ca2+ waves at higher [IP3] Local Ca2+ puffs at low [IP3] Marchant & Parker, EMBO J. 1999

  14. Temporal Profile Puff Blip Puff is triggered by blip Heather, Dargan, Shuai and Parker, Biophys J. 2006

  15. Multi-scale Ca2+ Signals

  16. Single IP3R Channel Model

  17. - Ca + Ca + Ca IP3 IP3 110 The IP3R channel model • Three independent and equivalent subunits. • Each subunit has 8 states: • The open subunit is • Channel is open when 3 subunits are open DeYoung & Keizer, PNAS 1992

  18. Tetrameric Structure of IP3R Hamada, et al, JBC 2003

  19. IP3 IP3R model with 4 Subunits • Each channel has four independent and equivalent subunits. • Open Channel 3 active subunits 4 active subunits

  20. The IP3R model with conformational change Shuai, et al, Biophys J. 2007

  21. Ca2+ Blipswith Single IP3R Channel

  22. Model Design 6mm Mobile Buffer 6mm Immobile Buffer Free Ca2+ 6mm

  23. - Ca 100 ? Random Number IP3 0 1 a2[Ca]dt a5[Ca]dt b1dt + Ca IP3 IP3 101 110 000 Markovian simulation of channel dynamics • Stochastic binding/unbinding dynamics: 110 a5[Ca]dt a2[Ca]dt b1dt Shuai & Jung, Biophys J 2002

  24. [Ca2+] distribution around the channel mouth 400mM [Ca2+] mM 20mM [Ca2+]~400mM [Ca2+]~20mM 15nm Cytosol ER

  25. Effects of Ca2+ Buffers Shuai, et al, Biophys J. 2008

  26. Slower Decay of [Ca2+]due to Immobile Buffer

  27. Faster Decay of [Ca2+]with Mobile Buffer

  28. Ca2+ Puffswith Clustered IP3R channels

  29. Puff Model 6mm 6mm L Immobile Buffer L : Cluster width N : Total number of open channels during a puff Free Ca2+ EGTA Fluo4 Dextran 6mm

  30. A Cluster of 9 IP3Rs

  31. Effects of Immobile Buffers

  32. Effects of Fast Mobile Buffer [BAPTA] mM

  33. [Ca2+] in the Cluster Time (ms)

  34. Modified [Ca2+] by BAPTA [BAPTA] mM Ruediger, Shuai, et al, Submitted

  35. Conclusion 1 Ca2+ Buffers function differently at single and clustered channel levels. • The open probability for a single IP3R: • increases with increasing immobile buffer • has little change with the mobile buffer • The open probability for a clustered IP3Rs: • has little change with the immobile buffer • shows a biphasic mode with the increase of fast mobile buffer (BAPTA).

  36. Ca2+ Wavesat Global Cell Level

  37. Ca2+ wave model Cytosol Free Ca2+ Stationary Buffer Mobile Buffer Channel cluster ER

  38. A stochastic Ca2+ model with clustered channels y x Cluster distance 3 mm Each cluster 36 channels

  39. With low [IP3] stimulus ? [Ca2+] [IP3]

  40. Cell size: Cluster distance 0.5mm Each cluster 1 channel Cluster distance 3mm Each cluster 36 channels Cluster distance 5mm Each cluster 100 channels What will happen if we change cluster distributions? Fixed !!! Total channels: 14,400

  41. Cluster distance 0.5mm Each cluster 1 channel No wave with low [IP3]at small cluster distance

  42. Cluster distance 5mm Each cluster 100 channels No wave with low [IP3]at large cluster distance

  43. Cluster distance 3mm Each cluster 36 channels At middle cluster distanceCa2+ waves generated with low [IP3]

  44. Noise-induced Ca2+ waves

  45. 1 4 9 16 25 36 64 100 Channel number per Cluster From Stochasticity To Periodicityat biologically realisticcluster distribution Characteristic time of self-correlation T Shuai and Jung, PNAS 2003

  46. With high [IP3] stimulus ? [Ca2+] [IP3]

  47. Puff-induced Ca2+ waves

  48. Bifurcation of calcium signal

  49. Interaction of channel noise and IP3 noise Channel noise only Channel noise only Channel noise + IP3 noise

  50. Restoration of Periodicity by Noise Suppressing Noise Liao, Jung, Shuai, PRE (2009)

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