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Osmolytes and Cell‐Volume Regulation: Physiological and Evolutionary Principles

George N. Somero, Paul H. Yancey

10.1002/cphy.cp140110

Source: Supplement 31: Handbook of Physiology, Cell Physiology

Originally published: 1997

Published online: January 2011

Full Article on Wiley Online Library



Abstract

The sections in this article are:

1 What Makes a Solute an Osmolyte?
2 The Basic Osmoregulatory Response: Conservation Paired with Change
3 Osmolyte Taxonomy: Evolutionary Convergence and Conservation
3.1 The Discovery of Organic Osmolytes
3.2 Polyols and Sugars
3.3 Free Amino Acids and Their Derivatives
3.4 Methylated Ammonium and Sulfonium Compounds
3.5 Urea and Urea with Methylamines
4 Osmolyte Effects: Perturbation, Stabilization, and Compatibility
4.1 Changes in Concentrations of Inorganic Ions Are Generally Perturbing of Biochemical Systems
4.2 Organic Osmolyte Compatibility with Biochemical Functions In Vitro
4.3 Organic Osmolyte Compatibility with Protein Structure In Vitro
4.4 Compatibility of Organic Osmolytes: In Vivo and Cell Culture Studies
5 Organic Osmolyte Effects: Counteracting Solute Systems
5.1 Counteracting Solute Effects In Vitro
5.2 Urea Counteraction in Living Systems
5.3 Salt Counteraction (Haloprotection)
5.4 Exceptions to Counteraction
6 Regulation of Osmolyte Concentrations
6.1 Interspecific Similarities in Basic Regulatory Strategies
6.2 Osmolyte Regulation in Bacteria and Plants
6.3 Osmolyte Regulation in Invertebrates
6.4 Osmolyte Regulation in Lower Vertebrates
6.5 The Mammalian Kidney
6.6 Stress Protein Induction in Hyperosmotic Stress
7 Mechanisms of Solute Effects—and Non‐Effects
7.1 The Hofmeister Series and Organic Osmolyte Structures
7.2 Preferential Exclusion of Compatible Osmolytes from the Protein Surface
7.3 Solute Interactions with Ligands in Solution
7.4 Nonreactivity of Modified Amino Acid Osmolytes
7.5 Monosaccharide Reactivity with Proteins
7.6 Favorable Effects of Compatible Solutes Not Related to Osmoregulation
7.7 Inorganic Ions: Perturbation and Compatibility
8 Evolutionary Perspectives
8.1 Macromolecular vs. “Micromolecular” Evolution
8.2 Evolution of Osmolyte Molecules: An Overview of Principles of Selection
8.3 Summary: The Adaptive Significance of Osmolyte System Evolution
Figure 1. Figure 1.

Time courses of change in intracellular contents of starch, glycerol, proline, and potassium ion in the unicellular green alga Chlorococcum submarinium exposed to rapid changes in salinity. Upper panel. Shift from 0.1 M to 0.5 M NaCl. Lower panel. Shift from 0.5 M to 0.1 M NaCl.

Redrawn from Blackwell and Gilmour 22
Figure 2. Figure 2.

Structures of the major classes of organic osmolytes.
Figure 3. Figure 3.

Effects of salts on in vitro activities of protein translation systems and enzymes. Upper left panel. Effects of KCl and K‐acetate on protein synthesis by a cell‐free translation system from mouse L‐cells.[Redrawn from Weber et al. 216]. Lower left panel. Effects of K‐acetate, glycine betaine, and proline on protein synthesis by a cell‐free translation system from wheat germ, using wheat leaf mRNA. [Redrawn from Wyn‐Jones 228.] Upper right panel. Effects of variations in KCl concentration on the maximal velocity of the pyruvate kinase reactions of diverse animals. [Redrawn from Bowlus and Somero 25.] Lower right panel. Effects of variations in NaCl concentration on activities of malate dehydrogenases from pig heart, a salt‐sensitive plant (Phaseolus vulgaris), and a salt‐tolerant plant (Atriplex spongiosa).

Redrawn from Greenway and Osmond 97
Figure 4. Figure 4.

Compatibility of organic osmolytes with in vitro biochemical functions. Upper left panel: Effects of solutes on the apparent Michaelis–Menten constant (Km) of phosphoenolpyruvate (PEP) for the pyruvate kinase reaction of the marine crab Pachygrapsus crassipes. [Redrawn from Bowlus and Somero 25.] Lower left panel. Effects of solutes on activity of malate dehydrogenase from leaves of Rhizophora mangle. [Redrawn from Sommer et al. 200.] Upper right and middle right panels. Effects of solutes on two mammalian renal enzymes, uricase (Km of uric acid) (upper) and argininosuccinase (Vmax) (middle). [Redrawn from Yancey 233.] Lower right panel. Effects of solutes on translation of wheat germ RNA by wheat germ ribosomes.

Redrawn from Gibson et al. 86
Figure 5. Figure 5.

The effects of organic solutes and inorganic ions on protein structure. Panel A. Solute effects on the thermal stability of bovine pancreatic ribonuclease. [Data from Bowlus and Somero 25, Yancey and Somero 239.] Panel B. Effects of proline, glycine betaine, and sorbitol on resistance of malate dehydrogenase from leaves of the plant Salsola soda to thermal denaturation. [Redrawn from Nikolopoulos and Manetas 161.] Panel C. Effects of different polyhydric alcohols on the resistance of chymotrypsin to heat inactivation. [Redrawn from Gekko and Morikawa 85.] Panel D. Effects of polyhydric alcohols on the thermal stability of lysozyme. [Redrawn from Fujita et al. 78.] Panel E. Effects of polyhydric alcohols on the rate of reassociation of urea‐denatured asparaginase.

Redrawn from Shifrin and Parrot 188
Figure 6. Figure 6.

The effects of the osomoprotectants choline‐O‐sulfate and glycine betaine on growth of E. coli cells in medium containing 0.65 M NaCl.

Redrawn from Hanson 105. β‐alanine betaine showed osmoprotection similar to that afforded by glycine betaine (not shown)
Figure 7. Figure 7.

A. Effects of exogenous tolrestat (Tol, an aldose reductase inhibitor), glycine betaine (Bet, 5 mM), or glucose on the number of successful colonies formed (from seeded individual cells) and cellular osmolyte contents (mmol/kg protein, normalized to control amount of sorbitol) of mammalian renal cells (PAP‐HT25) after 7–14 days in culture, in 500–550 mosmolar media (* = significant change). [Redrawn from Yancey et al. 236 and Moriyama et al. 154.] B. Effects of various dietary manipulations on osmolytes of rat renal inner medulla (contents in mmol/kg wet wet or mmol/kg protein, expressed as percent of appropriate control contents). Sorbinil: animals treated for 10 days with the aldose reductase inhibitor sorbinil in the diet at 40 mg/kg/d [data from Yancey et al. 238]; Galactosemia: animals with 50% dietary galactose for 10 days [data from Bondy et al. 23]; High Protein and Low Protein: animals on 50% or 4.5% protein, respectively (compared to 20% for controls) [data from Peterson et al. 163]. (* = significant change.) C. Effects of high glucose and the aldose reductase inhibitor tolrestat on cloning efficiency of PAP‐HT25 cells. At near normal osmolality high glucose inhibits cloning efficiency, but tolrestat offsets this effect through limiting the accumulation of sorbitol.

Redrawn after Yancey et al. 236
Figure 8. Figure 8.

Counteracting effects of urea and methylamines on in vitro biochemical systems. Panel A. Effects on Km of ADP for pyruvate kinase of the stingray (Urolophis halleri). Horizontal dashed line shows the 95% confidence interval around the control (no urea or methylamines) Km value. [Redrawn after Yancey and Somero 241.] Panel B. Effects on Vmax of the porcine kidney argininosuccinase reaction (unpublished data of T. Arnell, M. Blykowski, and P. H. Yancey). Panel C. Effects on activity of MDCK cell c‐AMP‐phosphodiesterase. [Data from Subramaniam and Jackson 204.] Rates are expressed relative to control (no added urea or methylamine). For all but the treatment “1 M urea + 0.5 M GPC” rates were significantly lower than control rates. Panel D. Effects on degree of phosphorylation of sarcoplasmic reticulum ATPase. [Data from deMeis and Inesi 61.] Panel E. Effects on thermal denaturation of bovine pancreatic ribonuclease. [Redrawn after Yancey and Somero 240]. Panel F. Labeling of sulfhydryl (−SH) groups of glutamate dehydrogenase (mammalian) by 4‐chloro‐7‐nitrobenzofurazan.

Redrawn after Yancey and Somero 240
Figure 9. Figure 9.

A. The effects of additions of NaCl, urea, glycerol, inositol, and glycine betaine to the growth medium on the colony‐forming efficiency of MDCK cells. Colony‐forming efficiency values are the number of colonies formed per number of single cells seeded on the growth plates, as normalized to control values (no test solutes added to the growth medium, which had an osmolality of 305 mosm/kg). Error bars represent SDs. Open squares connected by dashed lines represent glycine betaine added to cultures containing urea. (* = 2:1 ratio of urea to glycine betaine.) [Redrawn from Yancey and Burg 235.] B. GPC and urea contents in renal inner medulla of rats subjected to various combinations of dietary protein and salt load. Upper regression line: Diets are low protein/high salt (LPHS), normal protein/normal salt (NPNS), and high protein/reduced salt (HPRS). Lower regression line: Diets are all low salt (salt load lower than HS, NS, and RS diets on upper line). LP = low protein, RP = reduced protein (two separate experiments), HP = high protein, LC = low calorie diet (animals restricted to maintenance level of food).

Redrawn from Peterson et al. 163
Figure 10. Figure 10.

The protection of Aphanothece halophytica ribulosebisphosphate carboxylase/oxygenase activity from inhibition by KCl by organic solutes with different degrees of methylation.

Redrawn from Incharoensakdi et al. 119
Figure 11. Figure 11.

Left panels. Distributions of osmolytes in kidneys of antidiuretic rabbits (held without water for 2 days). The kidneys were cut into seven sections, from the outer cortex 7 to the tip of the inner medulla 7, as shown on the abscissa. “Total” in the bottom frame indicates the sum of methylamines + polyols. [Redrawn after Yancey and Burg 234.] Right panels. Correlations between renal contents of sodium and total methylamines and polyols for rat, rabbit, and wild rodents (mesic montane whole, Microtus montanus; deer mouse, Peromyscus m. gambeli; and xeric desert pocket mouse, Perognathus parvus). Each point represents four to seven animals. The upper points in each frame represent values for the inner medulla, the middle points are for the outer medulla, and the lowest points are for cortex. The upper panel is for antidiuretic animals and the lower panel is for diuretic animals (given water for 3 or more days); “x” values in lower panel are data replotted from upper panel.

Redrawn after Yancey 233
Figure 12. Figure 12.

Summary model of organic osmolyte accumulation and loss in mammalian renal medullary cells. The kinetics of the different processes differ. When extracellular osmolality is changed, activities of transporters and enzymes change slowly (left side of model), but permeability to solutes changes rapidly (right side of model).

Model after Burg 34
Figure 13. Figure 13.

Hofmeister series of ions.
Figure 14. Figure 14.

Preferential hydration model of Timasheff, illustrating distribution of water (open circles) and solute (closed circles) following equilibrium dialysis of a protein. Solutes that show preferential binding to a protein (that is, destabilizing solutes) occur at higher concentration inside dialysis bag than in solution outside bag (frame A). Structure‐stabilizing solutes are excluded from the water near protein and thus occur at higher concentrations outside dialysis bag (frame B). Because structure‐stabilizing solutes increase the surface tension of water, they also tend to be excluded from the water‐air interface.

Redrawn after Timasheff 205
Figure 15. Figure 15.

The opposite effects of binding solutes and preferentially excluded solutes on protein conformation, assembly, and solubility. Upper panel. Binding solute (S) favors unfolding of the protein (native coil) to the denatured state (random, extended coil). Lower panel. Preferentially excluded solute (S) favors conversion of unfolded protein (left) into compact, folded conformation of the protein (center). Higher concentrations of excluded solute favor enhanced protein‐protein interactions (right), and, at sufficiently high solute concentrations, protein precipitation.

Redrawn from Low 143


Figure 1.

Time courses of change in intracellular contents of starch, glycerol, proline, and potassium ion in the unicellular green alga Chlorococcum submarinium exposed to rapid changes in salinity. Upper panel. Shift from 0.1 M to 0.5 M NaCl. Lower panel. Shift from 0.5 M to 0.1 M NaCl.

Redrawn from Blackwell and Gilmour 22


Figure 2.

Structures of the major classes of organic osmolytes.



Figure 3.

Effects of salts on in vitro activities of protein translation systems and enzymes. Upper left panel. Effects of KCl and K‐acetate on protein synthesis by a cell‐free translation system from mouse L‐cells.[Redrawn from Weber et al. 216]. Lower left panel. Effects of K‐acetate, glycine betaine, and proline on protein synthesis by a cell‐free translation system from wheat germ, using wheat leaf mRNA. [Redrawn from Wyn‐Jones 228.] Upper right panel. Effects of variations in KCl concentration on the maximal velocity of the pyruvate kinase reactions of diverse animals. [Redrawn from Bowlus and Somero 25.] Lower right panel. Effects of variations in NaCl concentration on activities of malate dehydrogenases from pig heart, a salt‐sensitive plant (Phaseolus vulgaris), and a salt‐tolerant plant (Atriplex spongiosa).

Redrawn from Greenway and Osmond 97


Figure 4.

Compatibility of organic osmolytes with in vitro biochemical functions. Upper left panel: Effects of solutes on the apparent Michaelis–Menten constant (Km) of phosphoenolpyruvate (PEP) for the pyruvate kinase reaction of the marine crab Pachygrapsus crassipes. [Redrawn from Bowlus and Somero 25.] Lower left panel. Effects of solutes on activity of malate dehydrogenase from leaves of Rhizophora mangle. [Redrawn from Sommer et al. 200.] Upper right and middle right panels. Effects of solutes on two mammalian renal enzymes, uricase (Km of uric acid) (upper) and argininosuccinase (Vmax) (middle). [Redrawn from Yancey 233.] Lower right panel. Effects of solutes on translation of wheat germ RNA by wheat germ ribosomes.

Redrawn from Gibson et al. 86


Figure 5.

The effects of organic solutes and inorganic ions on protein structure. Panel A. Solute effects on the thermal stability of bovine pancreatic ribonuclease. [Data from Bowlus and Somero 25, Yancey and Somero 239.] Panel B. Effects of proline, glycine betaine, and sorbitol on resistance of malate dehydrogenase from leaves of the plant Salsola soda to thermal denaturation. [Redrawn from Nikolopoulos and Manetas 161.] Panel C. Effects of different polyhydric alcohols on the resistance of chymotrypsin to heat inactivation. [Redrawn from Gekko and Morikawa 85.] Panel D. Effects of polyhydric alcohols on the thermal stability of lysozyme. [Redrawn from Fujita et al. 78.] Panel E. Effects of polyhydric alcohols on the rate of reassociation of urea‐denatured asparaginase.

Redrawn from Shifrin and Parrot 188


Figure 6.

The effects of the osomoprotectants choline‐O‐sulfate and glycine betaine on growth of E. coli cells in medium containing 0.65 M NaCl.

Redrawn from Hanson 105. β‐alanine betaine showed osmoprotection similar to that afforded by glycine betaine (not shown)


Figure 7.

A. Effects of exogenous tolrestat (Tol, an aldose reductase inhibitor), glycine betaine (Bet, 5 mM), or glucose on the number of successful colonies formed (from seeded individual cells) and cellular osmolyte contents (mmol/kg protein, normalized to control amount of sorbitol) of mammalian renal cells (PAP‐HT25) after 7–14 days in culture, in 500–550 mosmolar media (* = significant change). [Redrawn from Yancey et al. 236 and Moriyama et al. 154.] B. Effects of various dietary manipulations on osmolytes of rat renal inner medulla (contents in mmol/kg wet wet or mmol/kg protein, expressed as percent of appropriate control contents). Sorbinil: animals treated for 10 days with the aldose reductase inhibitor sorbinil in the diet at 40 mg/kg/d [data from Yancey et al. 238]; Galactosemia: animals with 50% dietary galactose for 10 days [data from Bondy et al. 23]; High Protein and Low Protein: animals on 50% or 4.5% protein, respectively (compared to 20% for controls) [data from Peterson et al. 163]. (* = significant change.) C. Effects of high glucose and the aldose reductase inhibitor tolrestat on cloning efficiency of PAP‐HT25 cells. At near normal osmolality high glucose inhibits cloning efficiency, but tolrestat offsets this effect through limiting the accumulation of sorbitol.

Redrawn after Yancey et al. 236


Figure 8.

Counteracting effects of urea and methylamines on in vitro biochemical systems. Panel A. Effects on Km of ADP for pyruvate kinase of the stingray (Urolophis halleri). Horizontal dashed line shows the 95% confidence interval around the control (no urea or methylamines) Km value. [Redrawn after Yancey and Somero 241.] Panel B. Effects on Vmax of the porcine kidney argininosuccinase reaction (unpublished data of T. Arnell, M. Blykowski, and P. H. Yancey). Panel C. Effects on activity of MDCK cell c‐AMP‐phosphodiesterase. [Data from Subramaniam and Jackson 204.] Rates are expressed relative to control (no added urea or methylamine). For all but the treatment “1 M urea + 0.5 M GPC” rates were significantly lower than control rates. Panel D. Effects on degree of phosphorylation of sarcoplasmic reticulum ATPase. [Data from deMeis and Inesi 61.] Panel E. Effects on thermal denaturation of bovine pancreatic ribonuclease. [Redrawn after Yancey and Somero 240]. Panel F. Labeling of sulfhydryl (−SH) groups of glutamate dehydrogenase (mammalian) by 4‐chloro‐7‐nitrobenzofurazan.

Redrawn after Yancey and Somero 240


Figure 9.

A. The effects of additions of NaCl, urea, glycerol, inositol, and glycine betaine to the growth medium on the colony‐forming efficiency of MDCK cells. Colony‐forming efficiency values are the number of colonies formed per number of single cells seeded on the growth plates, as normalized to control values (no test solutes added to the growth medium, which had an osmolality of 305 mosm/kg). Error bars represent SDs. Open squares connected by dashed lines represent glycine betaine added to cultures containing urea. (* = 2:1 ratio of urea to glycine betaine.) [Redrawn from Yancey and Burg 235.] B. GPC and urea contents in renal inner medulla of rats subjected to various combinations of dietary protein and salt load. Upper regression line: Diets are low protein/high salt (LPHS), normal protein/normal salt (NPNS), and high protein/reduced salt (HPRS). Lower regression line: Diets are all low salt (salt load lower than HS, NS, and RS diets on upper line). LP = low protein, RP = reduced protein (two separate experiments), HP = high protein, LC = low calorie diet (animals restricted to maintenance level of food).

Redrawn from Peterson et al. 163


Figure 10.

The protection of Aphanothece halophytica ribulosebisphosphate carboxylase/oxygenase activity from inhibition by KCl by organic solutes with different degrees of methylation.

Redrawn from Incharoensakdi et al. 119


Figure 11.

Left panels. Distributions of osmolytes in kidneys of antidiuretic rabbits (held without water for 2 days). The kidneys were cut into seven sections, from the outer cortex 7 to the tip of the inner medulla 7, as shown on the abscissa. “Total” in the bottom frame indicates the sum of methylamines + polyols. [Redrawn after Yancey and Burg 234.] Right panels. Correlations between renal contents of sodium and total methylamines and polyols for rat, rabbit, and wild rodents (mesic montane whole, Microtus montanus; deer mouse, Peromyscus m. gambeli; and xeric desert pocket mouse, Perognathus parvus). Each point represents four to seven animals. The upper points in each frame represent values for the inner medulla, the middle points are for the outer medulla, and the lowest points are for cortex. The upper panel is for antidiuretic animals and the lower panel is for diuretic animals (given water for 3 or more days); “x” values in lower panel are data replotted from upper panel.

Redrawn after Yancey 233


Figure 12.

Summary model of organic osmolyte accumulation and loss in mammalian renal medullary cells. The kinetics of the different processes differ. When extracellular osmolality is changed, activities of transporters and enzymes change slowly (left side of model), but permeability to solutes changes rapidly (right side of model).

Model after Burg 34


Figure 13.

Hofmeister series of ions.



Figure 14.

Preferential hydration model of Timasheff, illustrating distribution of water (open circles) and solute (closed circles) following equilibrium dialysis of a protein. Solutes that show preferential binding to a protein (that is, destabilizing solutes) occur at higher concentration inside dialysis bag than in solution outside bag (frame A). Structure‐stabilizing solutes are excluded from the water near protein and thus occur at higher concentrations outside dialysis bag (frame B). Because structure‐stabilizing solutes increase the surface tension of water, they also tend to be excluded from the water‐air interface.

Redrawn after Timasheff 205


Figure 15.

The opposite effects of binding solutes and preferentially excluded solutes on protein conformation, assembly, and solubility. Upper panel. Binding solute (S) favors unfolding of the protein (native coil) to the denatured state (random, extended coil). Lower panel. Preferentially excluded solute (S) favors conversion of unfolded protein (left) into compact, folded conformation of the protein (center). Higher concentrations of excluded solute favor enhanced protein‐protein interactions (right), and, at sufficiently high solute concentrations, protein precipitation.

Redrawn from Low 143
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Article Title: Osmolytes and Cell‐Volume Regulation: Physiological and Evolutionary Principles
 

How to Cite

George N. Somero, Paul H. Yancey. Osmolytes and Cell‐Volume Regulation: Physiological and Evolutionary Principles. Compr Physiol 2011, Supplement 31: Handbook of Physiology, Cell Physiology: 441-484. First published in print 1997. doi: 10.1002/cphy.cp140110