Rheostasis (biology)

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Rheostasis refers to biochemical and physiological processes that, through graduated quantitative regulation, serve the adaptive needs of an organism facing internal or external environmental challenges. Physiological rheostasis operates much like an electrician’s rheostat graduates current. As discussed in the article on allostasis, the human living system persists in the living state not only through mechanisms that regulate constancy of critical biological variables and processes — homeostasis — but also through mechanisms that change the set-point ranges of biological variables and processes so as to adapt to changing, sometimes seriously threatening circumstances.

Biologists use the term 'on/off switch' when such set-point-range re-setting occurs in a binary ('on/off') type manner, and 'rheostat' when the regulatory mechanism operates in a graduated, or quantitative, manner. Biologists see one example of rheostasis in the phenomenon of quantitative gene expression regulation, when it occurs by continuously variable 'switches' quantitatively coupled to enzyme activity.^[1] ^[2] ^[3]

Rheostasis elucidates many other facets of mammalian physiology in relation to homeostasis, allostasis, and systems biology.^[4]

Lymphocyte persistence and expansion appear to be regulated by survival and programmed cell death (apoptosis) rheostatically in dividing cells by the interaction of two protein families, restraining lymphocyte expansion under adverse conditions.^[5]

The education of developing natural killer (NK) cells for optimal functional responsiveness at maturity — specialized to kill certain types of injurious target cells — appears to operate rheostatically, individual NK cells quantitatively tuned by graded inhibitory inputs during development.^[6]

References

↑
Hazzalin CA, Mahadevan LC. (2002) MAPK-regulated transcription: a continuously variable gene switch? Nat Rev Mol Cell Biol 3:30-40.
- Abstract: Switching mechanisms that control genes could be viewed either as stable binary switches, in which genes exist in 'on' or 'off' states; or as quantitative rheostat-like switches, in which the rate of transcription is continuously variable and coupled directly to the strength of intracellular signalling events. Here, we discuss the biological need for quantitative gene regulation and, using mitogen-activated protein kinase (MAPK)-controlled transcription as a model, assess the evidence for its existence and postulate mechanisms by which it might occur.
↑
Bardwell L. (2008) Signal transduction: turning a switch into a rheostat. Curr Biol 18:R910-R912.
- Note: Review and discussion of article by Satoe Takahashi and Peter M. Pryciak cited in Rheostasis (biology).
↑
Satoe Takahashi, Peter M. Pryciak. (2008) Membrane Localization of Scaffold Proteins Promotes Graded Signaling in the Yeast MAP Kinase Cascade. Current Biology 18(16):1184-1191.
- Abstract: Signaling through mitogen-activated protein kinase (MAPK) cascade pathways can show various input-output behaviors, including either switch-like or graded responses to increasing levels of stimulus. Prior studies suggest that switch-like behavior is promoted by positive feedback loops and nonprocessive phosphorylation reactions, but it is unclear whether graded signaling is a default behavior or whether it must be enforced by separate mechanisms. It has been hypothesized that scaffold proteins promote graded behavior….Here, we experimentally probe the determinants of graded signaling in the yeast mating MAPK pathway. We find that graded behavior is robust in that it resists perturbation by loss of several negative-feedback regulators. However, the pathway becomes switch-like when activated by a crosstalk stimulus that bypasses multiple upstream components. To dissect the contributing factors, we developed a method for gradually varying the signal input at different pathway steps in vivo. Input at the beginning of the kinase cascade produced a sharp, threshold-like response. Surprisingly, the scaffold protein Ste5 increased this threshold behavior when limited to the cytosol. However, signaling remained graded whenever Ste5 was allowed to function at the plasma membrane….The results suggest that the MAPK cascade module is inherently ultrasensitive but is converted to a graded system by the pathway-specific activation mechanism. Scaffold-mediated assembly of signaling complexes at the plasma membrane allows faithful propagation of weak signals, which consequently reduces pathway ultrasensitivity. These properties help shape the input-output properties of the system to fit the physiological context.
↑
Mrosovsky N. (1990) Rheostasis: the physiology of change. Oxford University Press. ISBN 0-19-506184-5.
- From the Preface: A point that is not generally appreciated is that the body does not always seek constancy of its internal environment. It does not always react in ways that prevent change. On the contrary, sometimes physiological mechanisms actively promote change….The scientific literature already contains numerous explanations couched in terms of changing set-points. One may read of the resetting of baroreceptors, osmostats, chemostats, and alphastats. Adjustments to thermostats, gonadostats, mechanostats and lipostats have already been proposed. But some name is needed to recognize the generality of these phenomena. Rheostasis is a convenient term for designating changes in regulated levels….This book is a reexamination and elaboration of the concept of homeostasis to include changes in regulated levels, rheostasis.
↑
Alves,N.L.; Derks,I.A.; Berk,E.; Spijker,R.; van Lier,R.A.; Eldering,E.. (2006) The Noxa/Mcl-1 axis regulates susceptibility to apoptosis under glucose limitation in dividing T cells. Immunity24(6):703-716. PMID 16782027.
- Throughout lymphocyte development, cellular persistence and expansion are tightly regulated by survival and apoptosis. Within the Bcl-2 family, distinct apoptogenic BH3-only members like Bid, Bim, and Puma appear to function in specific cell death pathways. We found that naive human T cells after mitogenic activation, apart from expected protective Bcl-2 members, also rapidly upregulate the BH3-only protein Noxa in a p53-independent fashion. The specific role of Noxa became apparent during glucose limitation and involves interaction with the labile Bcl-2 homolog Mcl-1. Knockdown of Noxa or Mcl-1 results in protection or susceptibility, respectively, to apoptosis induced by glucose deprivation. Declining Mcl-1 levels and apoptosis induction are inversely correlated to Noxa levels and prevented by readdition of glucose. We propose that the Noxa/Mcl-1 axis is an apoptosis rheostat in dividing cells, in a selective pathway that functions to restrain lymphocyte expansion and can be triggered by glucose deprivation.
↑
Brodin,P.; Karre,K.; Hoglund,P. (2009) NK cell education: not an on-off switch but a tunable rheostat. Trends Immuol. 30(4):143-149. PMID 19282243.
- Heterogeneity in the natural killer (NK) cell population is determined by variegated expression of polygenic and polymorphic receptors and distinct phenotypes and functions of NK cell subsets. Here, we outline an additional heterogeneity at the level of MHC-dependent education of NK cells. Based on data obtained using polychromatic flow cytometry and mice with single MHC class I alleles, we argue that NK cell responsiveness is tuned along a continuum determined by the strength of the inhibitory input received by the individual NK cell during education. This model has implications for the use of NK cells in therapeutic settings and affects interpretations of how NK cells control virus infections and regulate autoimmunity.

[hazzalin2002-1] Hazzalin CA, Mahadevan LC. (2002) MAPK-regulated transcription: a continuously variable gene switch? Nat Rev Mol Cell Biol 3:30-40.
Abstract: Switching mechanisms that control genes could be viewed either as stable binary switches, in which genes exist in 'on' or 'off' states; or as quantitative rheostat-like switches, in which the rate of transcription is continuously variable and coupled directly to the strength of intracellular signalling events. Here, we discuss the biological need for quantitative gene regulation and, using mitogen-activated protein kinase (MAPK)-controlled transcription as a model, assess the evidence for its existence and postulate mechanisms by which it might occur.

[2] Abstract: Switching mechanisms that control genes could be viewed either as stable binary switches, in which genes exist in 'on' or 'off' states; or as quantitative rheostat-like switches, in which the rate of transcription is continuously variable and coupled directly to the strength of intracellular signalling events. Here, we discuss the biological need for quantitative gene regulation and, using mitogen-activated protein kinase (MAPK)-controlled transcription as a model, assess the evidence for its existence and postulate mechanisms by which it might occur.

[2] Bardwell L. (2008) Signal transduction: turning a switch into a rheostat. Curr Biol 18:R910-R912.
Note: Review and discussion of article by Satoe Takahashi and Peter M. Pryciak cited in Rheostasis (biology).

[4] Note: Review and discussion of article by Satoe Takahashi and Peter M. Pryciak cited in Rheostasis (biology).

[3] Satoe Takahashi, Peter M. Pryciak. (2008) Membrane Localization of Scaffold Proteins Promotes Graded Signaling in the Yeast MAP Kinase Cascade. Current Biology 18(16):1184-1191.
Abstract: Signaling through mitogen-activated protein kinase (MAPK) cascade pathways can show various input-output behaviors, including either switch-like or graded responses to increasing levels of stimulus. Prior studies suggest that switch-like behavior is promoted by positive feedback loops and nonprocessive phosphorylation reactions, but it is unclear whether graded signaling is a default behavior or whether it must be enforced by separate mechanisms. It has been hypothesized that scaffold proteins promote graded behavior….Here, we experimentally probe the determinants of graded signaling in the yeast mating MAPK pathway. We find that graded behavior is robust in that it resists perturbation by loss of several negative-feedback regulators. However, the pathway becomes switch-like when activated by a crosstalk stimulus that bypasses multiple upstream components. To dissect the contributing factors, we developed a method for gradually varying the signal input at different pathway steps in vivo. Input at the beginning of the kinase cascade produced a sharp, threshold-like response. Surprisingly, the scaffold protein Ste5 increased this threshold behavior when limited to the cytosol. However, signaling remained graded whenever Ste5 was allowed to function at the plasma membrane….The results suggest that the MAPK cascade module is inherently ultrasensitive but is converted to a graded system by the pathway-specific activation mechanism. Scaffold-mediated assembly of signaling complexes at the plasma membrane allows faithful propagation of weak signals, which consequently reduces pathway ultrasensitivity. These properties help shape the input-output properties of the system to fit the physiological context.

[6] Abstract: Signaling through mitogen-activated protein kinase (MAPK) cascade pathways can show various input-output behaviors, including either switch-like or graded responses to increasing levels of stimulus. Prior studies suggest that switch-like behavior is promoted by positive feedback loops and nonprocessive phosphorylation reactions, but it is unclear whether graded signaling is a default behavior or whether it must be enforced by separate mechanisms. It has been hypothesized that scaffold proteins promote graded behavior….Here, we experimentally probe the determinants of graded signaling in the yeast mating MAPK pathway. We find that graded behavior is robust in that it resists perturbation by loss of several negative-feedback regulators. However, the pathway becomes switch-like when activated by a crosstalk stimulus that bypasses multiple upstream components. To dissect the contributing factors, we developed a method for gradually varying the signal input at different pathway steps in vivo. Input at the beginning of the kinase cascade produced a sharp, threshold-like response. Surprisingly, the scaffold protein Ste5 increased this threshold behavior when limited to the cytosol. However, signaling remained graded whenever Ste5 was allowed to function at the plasma membrane….The results suggest that the MAPK cascade module is inherently ultrasensitive but is converted to a graded system by the pathway-specific activation mechanism. Scaffold-mediated assembly of signaling complexes at the plasma membrane allows faithful propagation of weak signals, which consequently reduces pathway ultrasensitivity. These properties help shape the input-output properties of the system to fit the physiological context.

[4] Mrosovsky N. (1990) Rheostasis: the physiology of change. Oxford University Press. ISBN 0-19-506184-5.
From the Preface: A point that is not generally appreciated is that the body does not always seek constancy of its internal environment. It does not always react in ways that prevent change. On the contrary, sometimes physiological mechanisms actively promote change….The scientific literature already contains numerous explanations couched in terms of changing set-points. One may read of the resetting of baroreceptors, osmostats, chemostats, and alphastats. Adjustments to thermostats, gonadostats, mechanostats and lipostats have already been proposed. But some name is needed to recognize the generality of these phenomena. Rheostasis is a convenient term for designating changes in regulated levels….This book is a reexamination and elaboration of the concept of homeostasis to include changes in regulated levels, rheostasis.

[8] From the Preface: A point that is not generally appreciated is that the body does not always seek constancy of its internal environment. It does not always react in ways that prevent change. On the contrary, sometimes physiological mechanisms actively promote change….The scientific literature already contains numerous explanations couched in terms of changing set-points. One may read of the resetting of baroreceptors, osmostats, chemostats, and alphastats. Adjustments to thermostats, gonadostats, mechanostats and lipostats have already been proposed. But some name is needed to recognize the generality of these phenomena. Rheostasis is a convenient term for designating changes in regulated levels….This book is a reexamination and elaboration of the concept of homeostasis to include changes in regulated levels, rheostasis.

[5] Alves,N.L.; Derks,I.A.; Berk,E.; Spijker,R.; van Lier,R.A.; Eldering,E.. (2006) The Noxa/Mcl-1 axis regulates susceptibility to apoptosis under glucose limitation in dividing T cells. Immunity24(6):703-716. PMID 16782027.
Throughout lymphocyte development, cellular persistence and expansion are tightly regulated by survival and apoptosis. Within the Bcl-2 family, distinct apoptogenic BH3-only members like Bid, Bim, and Puma appear to function in specific cell death pathways. We found that naive human T cells after mitogenic activation, apart from expected protective Bcl-2 members, also rapidly upregulate the BH3-only protein Noxa in a p53-independent fashion. The specific role of Noxa became apparent during glucose limitation and involves interaction with the labile Bcl-2 homolog Mcl-1. Knockdown of Noxa or Mcl-1 results in protection or susceptibility, respectively, to apoptosis induced by glucose deprivation. Declining Mcl-1 levels and apoptosis induction are inversely correlated to Noxa levels and prevented by readdition of glucose. We propose that the Noxa/Mcl-1 axis is an apoptosis rheostat in dividing cells, in a selective pathway that functions to restrain lymphocyte expansion and can be triggered by glucose deprivation.

[10] Throughout lymphocyte development, cellular persistence and expansion are tightly regulated by survival and apoptosis. Within the Bcl-2 family, distinct apoptogenic BH3-only members like Bid, Bim, and Puma appear to function in specific cell death pathways. We found that naive human T cells after mitogenic activation, apart from expected protective Bcl-2 members, also rapidly upregulate the BH3-only protein Noxa in a p53-independent fashion. The specific role of Noxa became apparent during glucose limitation and involves interaction with the labile Bcl-2 homolog Mcl-1. Knockdown of Noxa or Mcl-1 results in protection or susceptibility, respectively, to apoptosis induced by glucose deprivation. Declining Mcl-1 levels and apoptosis induction are inversely correlated to Noxa levels and prevented by readdition of glucose. We propose that the Noxa/Mcl-1 axis is an apoptosis rheostat in dividing cells, in a selective pathway that functions to restrain lymphocyte expansion and can be triggered by glucose deprivation.

[6] Brodin,P.; Karre,K.; Hoglund,P. (2009) NK cell education: not an on-off switch but a tunable rheostat. Trends Immuol. 30(4):143-149. PMID 19282243.
Heterogeneity in the natural killer (NK) cell population is determined by variegated expression of polygenic and polymorphic receptors and distinct phenotypes and functions of NK cell subsets. Here, we outline an additional heterogeneity at the level of MHC-dependent education of NK cells. Based on data obtained using polychromatic flow cytometry and mice with single MHC class I alleles, we argue that NK cell responsiveness is tuned along a continuum determined by the strength of the inhibitory input received by the individual NK cell during education. This model has implications for the use of NK cells in therapeutic settings and affects interpretations of how NK cells control virus infections and regulate autoimmunity.

[12] Heterogeneity in the natural killer (NK) cell population is determined by variegated expression of polygenic and polymorphic receptors and distinct phenotypes and functions of NK cell subsets. Here, we outline an additional heterogeneity at the level of MHC-dependent education of NK cells. Based on data obtained using polychromatic flow cytometry and mice with single MHC class I alleles, we argue that NK cell responsiveness is tuned along a continuum determined by the strength of the inhibitory input received by the individual NK cell during education. This model has implications for the use of NK cells in therapeutic settings and affects interpretations of how NK cells control virus infections and regulate autoimmunity.

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Rheostasis (biology)

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