Limits...
Dose-to-duration encoding and signaling beyond saturation in intracellular signaling networks.

Behar M, Hao N, Dohlman HG, Elston TC - PLoS Comput. Biol. (2008)

Bottom Line: We demonstrate that modulation of signal duration increases the range of stimulus concentrations for which dose-dependent responses are possible; this increased dynamic range produces the counterintuitive result of "signaling beyond saturation" in which dose-dependent responses are still possible after apparent saturation of the receptors.The ability of signaling pathways to convert stimulus strength into signal duration results directly from the nonlinear nature of these systems and emphasizes the importance of considering the dynamic properties of signaling pathways when characterizing their behavior.Understanding how signaling pathways encode and transmit quantitative information about the external environment will not only deepen our understanding of these systems but also provide insight into how to reestablish proper function of pathways that have become dysregulated by disease.

View Article: PubMed Central - PubMed

Affiliation: Department of Physics, University of North Carolina Chapel Hill, Chapel Hill, North Carolina, United States of America.

ABSTRACT
The cellular response elicited by an environmental cue typically varies with the strength of the stimulus. For example, in the yeast Saccharomyces cerevisiae, the concentration of mating pheromone determines whether cells undergo vegetative growth, chemotropic growth, or mating. This implies that the signaling pathways responsible for detecting the stimulus and initiating a response must transmit quantitative information about the intensity of the signal. Our previous experimental results suggest that yeast encode pheromone concentration as the duration of the transmitted signal. Here we use mathematical modeling to analyze possible biochemical mechanisms for performing this "dose-to-duration" conversion. We demonstrate that modulation of signal duration increases the range of stimulus concentrations for which dose-dependent responses are possible; this increased dynamic range produces the counterintuitive result of "signaling beyond saturation" in which dose-dependent responses are still possible after apparent saturation of the receptors. We propose a mechanism for dose-to-duration encoding in the yeast pheromone pathway that is consistent with current experimental observations. Most previous investigations of information processing by signaling pathways have focused on amplitude encoding without considering temporal aspects of signal transduction. Here we demonstrate that dose-to-duration encoding provides cells with an alternative mechanism for processing and transmitting quantitative information about their surrounding environment. The ability of signaling pathways to convert stimulus strength into signal duration results directly from the nonlinear nature of these systems and emphasizes the importance of considering the dynamic properties of signaling pathways when characterizing their behavior. Understanding how signaling pathways encode and transmit quantitative information about the external environment will not only deepen our understanding of these systems but also provide insight into how to reestablish proper function of pathways that have become dysregulated by disease.

Show MeSH

Related in: MedlinePlus

Dose-to-duration encoding by negative feedback.The units of concentration are arbitrary and time is measured in minutes. The responses are normalized to the total concentration of the respective proteins. (A) Response curves for species K shown in the absence of the negative regulator X (left curve) and in the presence of maximal X activity (right curve). (B) Displacement of the response curve during a signaling event. Blue curve: KK* level used to generate the curves in (C). (C) Time profiles of [K*] (red curve) and [X*] (green curve, left panel) and the activation rate of K (red curve) and deactivation rate of K* (dashed blue curve, right). Note that after an initial spike in the activation rate, the two rates roughly equalize satisfying the quasi-equilibrium condition. The system adapts when the activation rate can no longer increase and compensate for the increasing X activity. (D) An expanded version of the response curves shown in (A) indicating the four possible operational regimes. (E) Time courses of K activity illustrating the four operational regimes. (F) Signal duration (defined as time between half maxima) vs. KK* concentration. Regimes I and II are shown. (G) Same as (E) except the different regimes are now shown on the same graph.
© Copyright Policy
Related In: Results  -  Collection


getmorefigures.php?uid=PMC2543107&req=5

pcbi-1000197-g004: Dose-to-duration encoding by negative feedback.The units of concentration are arbitrary and time is measured in minutes. The responses are normalized to the total concentration of the respective proteins. (A) Response curves for species K shown in the absence of the negative regulator X (left curve) and in the presence of maximal X activity (right curve). (B) Displacement of the response curve during a signaling event. Blue curve: KK* level used to generate the curves in (C). (C) Time profiles of [K*] (red curve) and [X*] (green curve, left panel) and the activation rate of K (red curve) and deactivation rate of K* (dashed blue curve, right). Note that after an initial spike in the activation rate, the two rates roughly equalize satisfying the quasi-equilibrium condition. The system adapts when the activation rate can no longer increase and compensate for the increasing X activity. (D) An expanded version of the response curves shown in (A) indicating the four possible operational regimes. (E) Time courses of K activity illustrating the four operational regimes. (F) Signal duration (defined as time between half maxima) vs. KK* concentration. Regimes I and II are shown. (G) Same as (E) except the different regimes are now shown on the same graph.

Mentions: We focus primarily on the negative feedback system depicted by the left diagram in Figure 3B, but the results that follow easily generalize to the other architectures. The equations that describe this model are given in the Methods. To understand how this system performs the dose-to-duration transformation, it is helpful to consider the steady-state response curve of K as a function of the activity of the upstream component KK in the absence and presence of the negative regulator X. In Figure 4A, the left curve corresponds to the case in which X has been deleted. When present, the effect of the negative regulator X is to shift the signal-response curve to higher active KK concentrations. Accordingly, the right curve shown in Figure 4A corresponds to the case in which X is maximally activated.


Dose-to-duration encoding and signaling beyond saturation in intracellular signaling networks.

Behar M, Hao N, Dohlman HG, Elston TC - PLoS Comput. Biol. (2008)

Dose-to-duration encoding by negative feedback.The units of concentration are arbitrary and time is measured in minutes. The responses are normalized to the total concentration of the respective proteins. (A) Response curves for species K shown in the absence of the negative regulator X (left curve) and in the presence of maximal X activity (right curve). (B) Displacement of the response curve during a signaling event. Blue curve: KK* level used to generate the curves in (C). (C) Time profiles of [K*] (red curve) and [X*] (green curve, left panel) and the activation rate of K (red curve) and deactivation rate of K* (dashed blue curve, right). Note that after an initial spike in the activation rate, the two rates roughly equalize satisfying the quasi-equilibrium condition. The system adapts when the activation rate can no longer increase and compensate for the increasing X activity. (D) An expanded version of the response curves shown in (A) indicating the four possible operational regimes. (E) Time courses of K activity illustrating the four operational regimes. (F) Signal duration (defined as time between half maxima) vs. KK* concentration. Regimes I and II are shown. (G) Same as (E) except the different regimes are now shown on the same graph.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2543107&req=5

pcbi-1000197-g004: Dose-to-duration encoding by negative feedback.The units of concentration are arbitrary and time is measured in minutes. The responses are normalized to the total concentration of the respective proteins. (A) Response curves for species K shown in the absence of the negative regulator X (left curve) and in the presence of maximal X activity (right curve). (B) Displacement of the response curve during a signaling event. Blue curve: KK* level used to generate the curves in (C). (C) Time profiles of [K*] (red curve) and [X*] (green curve, left panel) and the activation rate of K (red curve) and deactivation rate of K* (dashed blue curve, right). Note that after an initial spike in the activation rate, the two rates roughly equalize satisfying the quasi-equilibrium condition. The system adapts when the activation rate can no longer increase and compensate for the increasing X activity. (D) An expanded version of the response curves shown in (A) indicating the four possible operational regimes. (E) Time courses of K activity illustrating the four operational regimes. (F) Signal duration (defined as time between half maxima) vs. KK* concentration. Regimes I and II are shown. (G) Same as (E) except the different regimes are now shown on the same graph.
Mentions: We focus primarily on the negative feedback system depicted by the left diagram in Figure 3B, but the results that follow easily generalize to the other architectures. The equations that describe this model are given in the Methods. To understand how this system performs the dose-to-duration transformation, it is helpful to consider the steady-state response curve of K as a function of the activity of the upstream component KK in the absence and presence of the negative regulator X. In Figure 4A, the left curve corresponds to the case in which X has been deleted. When present, the effect of the negative regulator X is to shift the signal-response curve to higher active KK concentrations. Accordingly, the right curve shown in Figure 4A corresponds to the case in which X is maximally activated.

Bottom Line: We demonstrate that modulation of signal duration increases the range of stimulus concentrations for which dose-dependent responses are possible; this increased dynamic range produces the counterintuitive result of "signaling beyond saturation" in which dose-dependent responses are still possible after apparent saturation of the receptors.The ability of signaling pathways to convert stimulus strength into signal duration results directly from the nonlinear nature of these systems and emphasizes the importance of considering the dynamic properties of signaling pathways when characterizing their behavior.Understanding how signaling pathways encode and transmit quantitative information about the external environment will not only deepen our understanding of these systems but also provide insight into how to reestablish proper function of pathways that have become dysregulated by disease.

View Article: PubMed Central - PubMed

Affiliation: Department of Physics, University of North Carolina Chapel Hill, Chapel Hill, North Carolina, United States of America.

ABSTRACT
The cellular response elicited by an environmental cue typically varies with the strength of the stimulus. For example, in the yeast Saccharomyces cerevisiae, the concentration of mating pheromone determines whether cells undergo vegetative growth, chemotropic growth, or mating. This implies that the signaling pathways responsible for detecting the stimulus and initiating a response must transmit quantitative information about the intensity of the signal. Our previous experimental results suggest that yeast encode pheromone concentration as the duration of the transmitted signal. Here we use mathematical modeling to analyze possible biochemical mechanisms for performing this "dose-to-duration" conversion. We demonstrate that modulation of signal duration increases the range of stimulus concentrations for which dose-dependent responses are possible; this increased dynamic range produces the counterintuitive result of "signaling beyond saturation" in which dose-dependent responses are still possible after apparent saturation of the receptors. We propose a mechanism for dose-to-duration encoding in the yeast pheromone pathway that is consistent with current experimental observations. Most previous investigations of information processing by signaling pathways have focused on amplitude encoding without considering temporal aspects of signal transduction. Here we demonstrate that dose-to-duration encoding provides cells with an alternative mechanism for processing and transmitting quantitative information about their surrounding environment. The ability of signaling pathways to convert stimulus strength into signal duration results directly from the nonlinear nature of these systems and emphasizes the importance of considering the dynamic properties of signaling pathways when characterizing their behavior. Understanding how signaling pathways encode and transmit quantitative information about the external environment will not only deepen our understanding of these systems but also provide insight into how to reestablish proper function of pathways that have become dysregulated by disease.

Show MeSH
Related in: MedlinePlus