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Shuai Zeng, Bing Li, Shaoqun Zeng, Shangbin Chen  Biophysical Journal 

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1 Simulation of Spontaneous Ca2+ Oscillations in Astrocytes Mediated by Voltage-Gated Calcium Channels 
Shuai Zeng, Bing Li, Shaoqun Zeng, Shangbin Chen  Biophysical Journal  Volume 97, Issue 9, Pages (November 2009) DOI: /j.bpj Copyright © 2009 Biophysical Society Terms and Conditions

2 Figure 1 Schematic drawing of voltage-gated calcium channels (VGCCs) mediating Ca2+ oscillations. The main features within the astrocyte were referred to in Lavrentovich and Hemkin's model (26). Different VGCCs (T, L, N, R, P, and Q) form Ca2+ influx JVGCC from the extracellular space (ECS) to the intracellular space (ICS). Cytoplasmic Ca2+ enhances the production of inositol 1,4,5-triphosphate (IP3) catalyzed by phospholipase C (PLC). Cytoplasmic Ca2+ and IP3 mediate IP3 receptors (IP3R), inducing Ca2+ flow JCICR out of the endoplasmic reticulum (ER). JSERCA represents ER Ca2+ filling by the sarcoplasmic/endoplasmic reticulum calcium ATPase (SERCA). Two “leak” arrows indicate the leak flux due to the concentration gradient. Biophysical Journal  , DOI: ( /j.bpj ) Copyright © 2009 Biophysical Society Terms and Conditions

3 Figure 2 Steady-state activation fraction of different voltage-gated calcium channels. The activation fraction is the normalized product of the activation and inactivation variables m and h from every type of channel. The cytoplasmic Ca2+ concentration was fixed at 0.1 μM for considering the Ca2+ concentration dependence. Biophysical Journal  , DOI: ( /j.bpj ) Copyright © 2009 Biophysical Society Terms and Conditions

4 Figure 3 Typical spontaneous Ca2+ oscillations from the computational study. From top to bottom, the three plots correspond to oscillations in cytoplasmic Ca2+, ER Ca2+, and cytoplasmic IP3. All three variables have the same frequency but different peak times (details are shown in Fig. 4). Biophysical Journal  , DOI: ( /j.bpj ) Copyright © 2009 Biophysical Society Terms and Conditions

5 Figure 4 Normalized plot of the three variables in Fig. 3, during one period of Ca2+ oscillations. Their peak time points are ranked as ER Ca2+, cytoplasmic Ca2+, and cytoplasmic IP3. Before the sudden increase in cytoplasmic Ca2+, ER Ca2+ increased slowly. Biophysical Journal  , DOI: ( /j.bpj ) Copyright © 2009 Biophysical Society Terms and Conditions

6 Figure 5 The occurrence of Ca2+ oscillation depends on the membrane potential. When the membrane potential is <−70.0 mV or >−64.9 mV, there is no Ca2+ oscillation. Within −70.0 to −64.9 mV, the frequency and amplitude of Ca2+ oscillations change with the membrane potential. Biophysical Journal  , DOI: ( /j.bpj ) Copyright © 2009 Biophysical Society Terms and Conditions

7 Figure 6 (A) Bifurcation diagram of Ca2+ oscillations as a function of membrane potential. Sustained Ca2+ oscillations occurred in the potential range of −70.0 to −64.9 mV, where the maximum and minimum of Ca2+ oscillations were plotted. The dashed line refers to the unstable steady state. Out of the oscillatory domain, the system evolved into a stable steady state. (B) Frequency of Ca2+ oscillations versus membrane potential. Biophysical Journal  , DOI: ( /j.bpj ) Copyright © 2009 Biophysical Society Terms and Conditions

8 Figure 7 Dependence of Ca2+ oscillations on extracellular Ca2+ concentration. Ca2+ oscillations stopped when the extracellular Ca2+ concentration was too low or too high. From 0.1 to 1500 μM, the frequency of Ca2+ oscillations increased with a rise in extracellular Ca2+ concentration. Biophysical Journal  , DOI: ( /j.bpj ) Copyright © 2009 Biophysical Society Terms and Conditions

9 Figure 8 Amplitude and frequency of Ca2+ oscillations versus temperature. In the temperature range of 20–37°C, both the amplitude (indicated as an asterisk) and frequency (dotted line) decreased with temperature. Biophysical Journal  , DOI: ( /j.bpj ) Copyright © 2009 Biophysical Society Terms and Conditions

10 Figure 9 Dependence of Ca2+ oscillations on different VGCCs. T- and R-type of VGCCs showed little effect on Ca2+ oscillations. L- and N-type of VGCCs had effective influence on Ca2+ oscillations. Blocking the L-type VGCC decreased Ca2+ oscillations to 51.4% of control, while blocking the N-type decreased Ca2+ oscillations to 73.6%. Biophysical Journal  , DOI: ( /j.bpj ) Copyright © 2009 Biophysical Society Terms and Conditions

11 Figure 10 Contribution of Ca2+ entry through different VGCCs. All the results were obtained with the membrane potential of −65 mV. JVGCC was the total flux from all the VGCCs, and JT, JL, JN, and JR indicate the partial flux through the T-, L-, N-, and R-type channel, respectively. Biophysical Journal  , DOI: ( /j.bpj ) Copyright © 2009 Biophysical Society Terms and Conditions


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