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Expression of excess receptors and negative feedback control of signal pathways are required for rapid activation and prompt cessation of signal transduction.

Kobayashi H, Azuma R, Yasunaga T - Cell Commun. Signal (2009)

Bottom Line: Intracellular signal proteins are activated at a high level soon after ligand binding, and the activation level decreases in a negative feedback manner without ligand clearance.An initial increase in active cytosolic signal proteins to a high level is required for rapid activation of cellular signal pathways, and a low level of active signal proteins is essential for the rapid shutdown of signal pathways after ligand clearance.The present kinetic analysis revealed that excess receptors and negative feedback regulation promote activation and cessation of signal transduction with a low amount of extracellular ligand.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Biochemistry, Graduate School of Pharmaceutical Sciences, Chiba University, 1-8-1, Inohana, Chuo-ku, Chiba 260-8675, Japan. hiroshi@p.chiba-u.ac.jp.

ABSTRACT

Background: Cellular signal transduction is initiated by the binding of extracellular ligands to membrane receptors. Receptors are often expressed in excess, and cells are activated when a small number of receptors bind ligands. Intracellular signal proteins are activated at a high level soon after ligand binding, and the activation level decreases in a negative feedback manner without ligand clearance. Why are excess receptors required? What is the physiological significance of the negative feedback regulation?

Results: To answer these questions, we developed a Monte Carlo simulation program to kinetically analyze signal pathways using the model in which ligands are bound to receptors and then membrane complexes with other membrane proteins are formed. Our simulation results showed that excess receptors are not required for cell activation when the dissociation constant (Kd) of the ligand-receptor complex is 10-10 M or less. However, such low Kd values cause delayed signal shutdown after ligand clearance from the extracellular space. In contrast, when the Kd was 10-8 M and the ligand level was less than 1 muM, excess receptors were required for prompt signal propagation and rapid signal cessation after ligand clearance. An initial increase in active cytosolic signal proteins to a high level is required for rapid activation of cellular signal pathways, and a low level of active signal proteins is essential for the rapid shutdown of signal pathways after ligand clearance.

Conclusion: The present kinetic analysis revealed that excess receptors and negative feedback regulation promote activation and cessation of signal transduction with a low amount of extracellular ligand.

No MeSH data available.


Related in: MedlinePlus

Cell model for simulation, molecular diffusion rates, and receptor movement. (A) The cell model used for simulation. See text for details. (B) Distribution of diffusion rates (υ). For details, see text. (C,D) Movement of R was plotted for 1 × 104 steps at intervals of 10 steps. The diffusion rates of R used were υ(C) and 0.1υ(D). The numbers of subspaces were 600 × 600 × 1 (C) and 300 × 300 × 1 (D).
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Figure 1: Cell model for simulation, molecular diffusion rates, and receptor movement. (A) The cell model used for simulation. See text for details. (B) Distribution of diffusion rates (υ). For details, see text. (C,D) Movement of R was plotted for 1 × 104 steps at intervals of 10 steps. The diffusion rates of R used were υ(C) and 0.1υ(D). The numbers of subspaces were 600 × 600 × 1 (C) and 300 × 300 × 1 (D).

Mentions: In the present study, we assumed a simplified model in which the cell surface is represented as a 2-dimensional plane between 3-dimensional extracellular and cytosolic spaces (Figure 1-I). The cell surface and the extracellular space were divided into subspaces. Real-type pseudo uniform random numbers (N) with the range 0 ≤ N < 1 were generated as reported previously [15]. Each molecule was assumed to undergo random motion with a diffusion rate (υ) that has a pseudo-normal probability distribution from 0 to 100. υ was generated as described in Table 1, and the resulting distribution is shown in Figure 1-II. Each molecule has υ and its direction of movement (positive or negative direction on each axis), and molecules move into their neighboring subspace when τ < υ, where τ is a pseudo uniform random number (0 ≤ τ < 100) obtained as described in Table 1. υ was defined as the diffusion rate of the extracellular ligand and cytosolic proteins, and 0.1υ was used for the rate of membrane proteins and their complexes with the ligand. When υ = 0, the molecules remained in the same subspace. The diffusion rates and directions were updated for 1% of all molecules at each step, and this sample population was selected randomly. The trajectories of the receptors are shown in Figure 1-III and 1-IV. We assumed periodic boundary conditions; i.e., a molecule moved to the opposite side when it reached the boundary of its simulation box, except that when it reached the cell surface or its opposite boundary, it was reflected in the mirror direction.


Expression of excess receptors and negative feedback control of signal pathways are required for rapid activation and prompt cessation of signal transduction.

Kobayashi H, Azuma R, Yasunaga T - Cell Commun. Signal (2009)

Cell model for simulation, molecular diffusion rates, and receptor movement. (A) The cell model used for simulation. See text for details. (B) Distribution of diffusion rates (υ). For details, see text. (C,D) Movement of R was plotted for 1 × 104 steps at intervals of 10 steps. The diffusion rates of R used were υ(C) and 0.1υ(D). The numbers of subspaces were 600 × 600 × 1 (C) and 300 × 300 × 1 (D).
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC2666736&req=5

Figure 1: Cell model for simulation, molecular diffusion rates, and receptor movement. (A) The cell model used for simulation. See text for details. (B) Distribution of diffusion rates (υ). For details, see text. (C,D) Movement of R was plotted for 1 × 104 steps at intervals of 10 steps. The diffusion rates of R used were υ(C) and 0.1υ(D). The numbers of subspaces were 600 × 600 × 1 (C) and 300 × 300 × 1 (D).
Mentions: In the present study, we assumed a simplified model in which the cell surface is represented as a 2-dimensional plane between 3-dimensional extracellular and cytosolic spaces (Figure 1-I). The cell surface and the extracellular space were divided into subspaces. Real-type pseudo uniform random numbers (N) with the range 0 ≤ N < 1 were generated as reported previously [15]. Each molecule was assumed to undergo random motion with a diffusion rate (υ) that has a pseudo-normal probability distribution from 0 to 100. υ was generated as described in Table 1, and the resulting distribution is shown in Figure 1-II. Each molecule has υ and its direction of movement (positive or negative direction on each axis), and molecules move into their neighboring subspace when τ < υ, where τ is a pseudo uniform random number (0 ≤ τ < 100) obtained as described in Table 1. υ was defined as the diffusion rate of the extracellular ligand and cytosolic proteins, and 0.1υ was used for the rate of membrane proteins and their complexes with the ligand. When υ = 0, the molecules remained in the same subspace. The diffusion rates and directions were updated for 1% of all molecules at each step, and this sample population was selected randomly. The trajectories of the receptors are shown in Figure 1-III and 1-IV. We assumed periodic boundary conditions; i.e., a molecule moved to the opposite side when it reached the boundary of its simulation box, except that when it reached the cell surface or its opposite boundary, it was reflected in the mirror direction.

Bottom Line: Intracellular signal proteins are activated at a high level soon after ligand binding, and the activation level decreases in a negative feedback manner without ligand clearance.An initial increase in active cytosolic signal proteins to a high level is required for rapid activation of cellular signal pathways, and a low level of active signal proteins is essential for the rapid shutdown of signal pathways after ligand clearance.The present kinetic analysis revealed that excess receptors and negative feedback regulation promote activation and cessation of signal transduction with a low amount of extracellular ligand.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Biochemistry, Graduate School of Pharmaceutical Sciences, Chiba University, 1-8-1, Inohana, Chuo-ku, Chiba 260-8675, Japan. hiroshi@p.chiba-u.ac.jp.

ABSTRACT

Background: Cellular signal transduction is initiated by the binding of extracellular ligands to membrane receptors. Receptors are often expressed in excess, and cells are activated when a small number of receptors bind ligands. Intracellular signal proteins are activated at a high level soon after ligand binding, and the activation level decreases in a negative feedback manner without ligand clearance. Why are excess receptors required? What is the physiological significance of the negative feedback regulation?

Results: To answer these questions, we developed a Monte Carlo simulation program to kinetically analyze signal pathways using the model in which ligands are bound to receptors and then membrane complexes with other membrane proteins are formed. Our simulation results showed that excess receptors are not required for cell activation when the dissociation constant (Kd) of the ligand-receptor complex is 10-10 M or less. However, such low Kd values cause delayed signal shutdown after ligand clearance from the extracellular space. In contrast, when the Kd was 10-8 M and the ligand level was less than 1 muM, excess receptors were required for prompt signal propagation and rapid signal cessation after ligand clearance. An initial increase in active cytosolic signal proteins to a high level is required for rapid activation of cellular signal pathways, and a low level of active signal proteins is essential for the rapid shutdown of signal pathways after ligand clearance.

Conclusion: The present kinetic analysis revealed that excess receptors and negative feedback regulation promote activation and cessation of signal transduction with a low amount of extracellular ligand.

No MeSH data available.


Related in: MedlinePlus