The ability to control cell volume is pivotal for cell function. Cell volume perturbation elicits a wide array of signaling events, leading to protective (e.g., cytoskeletal rearrangement) and adap...

Physiology of cell volume regulation in vertebrates.

The maintenance of a constant volume in the face of extracellular and intracellular osmotic perturbation is essential for the normal function and survival of animal cells. Osmotically swollen cells restore their volume, exhibiting a regulatory volume decrease by releasing intracellular K+, Cl-, organic solutes, and obligated water. In many cell types, the volume regulatory effluxes of Cl- and some organic osmolytes are known to be induced by swelling-induced activation of anion channels that are characterized by their moderate outward rectification, cytosolic ATP dependency, and intermediate unitary conductance (10-100 pS). Recently, simultaneous measurements of cell size by light microscopy and whole cell Cl- current have shown that the Cl- current density is proportionally increased with an increase in the outer surface area, which is mainly achieved through unfolding of membrane invaginations by volume expansion. Thus this anion channel can somehow sense volume expansion and can be called the volume expansion-sensing outwardly rectifying (VSOR) anion channel. Its molecular identity and activation mechanism are yet to be elucidated. Three cloned proteins, ClC-2, P-glycoprotein, and pIcln, have been proposed as candidates for the VSOR anion channel. The unitary conductance, voltage dependency, anion selectivity, pH dependency, and pharmacology of the VSOR anion channel are distinct from the ClC-2 Cl- channel, which is also known to be sensitive to volume changes. Recent patch-clamp studies in combination with molecular biological techniques have shown that P-glycoprotein is not itself the channel protein but is a regulator of its volume sensitivity. Although there is still debate about another candidate protein, pIcln, the most recent study has suggested that this is likely to be a regulator of some other distinct Cl- channel. Identification of the VSOR anion channel protein per se, its volume-sensing mechanism, and its accessory/regulatory proteins at the molecular level is currently a subject of utmost physiological importance.

Volume expansion-sensing outward-rectifier Cl- channel: fresh start to the molecular identity and volume sensor.

Aldehydes are organic compounds that are widespread in nature. They can be formed endogenously by lipid peroxidation (LPO), carbohydrate or metabolism ascorbate autoxidation, amine oxidases, cytochrome P-450s, or myeloperoxidase-catalyzed metabolic activation. This review compares the reactivity of many aldehydes towards biomolecules particularly macromolecules. Furthermore, it includes not only aldehydes of environmental or occupational concerns but also dietary aldehydes and aldehydes formed endogenously by intermediary metabolism. Drugs that are aldehydes or form reactive aldehyde metabolites that cause side-effect toxicity are also included. The effects of these aldehydes on biological function, their contribution to human diseases, and the role of nucleic acid and protein carbonylation/oxidation in mutagenicity and cytotoxicity mechanisms, respectively, as well as carbonyl signal transduction and gene expression, are reviewed. Aldehyde metabolic activation and detoxication by metabolizing enzymes are also reviewed, as well as the toxicological and anticancer therapeutic effects of metabolizing enzyme inhibitors. The human health risks from clinical and animal research studies are reviewed, including aldehydes as haptens in allergenic hypersensitivity diseases, respiratory allergies, and idiosyncratic drug toxicity; the potential carcinogenic risks of the carbonyl body burden; and the toxic effects of aldehydes in liver disease, embryo toxicity/teratogenicity, diabetes/hypertension, sclerosing peritonitis, cerebral ischemia/neurodegenerative diseases, and other aging-associated diseases.

Aldehyde sources, metabolism, molecular toxicity mechanisms, and possible effects on human health.

Arthur Chickering is Distinguished Professor of Higher Education at Memphis State University. On leave from the Directorship of the Center for the Study of Higher Education at Memphis State, he is Visiting Professor at George Mason University. Zelda Gamson is a sociologist who holds appointments at the John W. McCormack Institute of Public Affairs at the University of Massachusetts-Boston and in the Center for the Study of Higher and Postsecondary Education at the University of Michigan.

Seven Principles for Good Practice in Undergraduate Education: Faculty Inventory. Institutional Inventory.

Properties of volume-regulated anion channels in mammalian cells

1. Changes in relative cell volume in response to hypotonic solutions and glucose were studied in single isolated rat pancreatic beta-cells using a video-imaging technique. beta-cell electrical activity was recorded under similar conditions using the perforated patch technique. 2. Exposure of beta-cells to hypotonic solutions (10 and 33% hypotonicity) caused an immediate increase in cell volume to relative values of 1.09 and 1.33, respectively. This was followed by a gradual regulatory volume decrease. 3. Raising the concentration of glucose from 4 to 20 mM or 12 mM (with substitution of mannitol) increased beta-cell volume by 12 and 10%, respectively. This effect of glucose persisted when CO2+ was added to inhibit insulin release. Glucose-induced volume increases were sustained for the duration of exposure to elevated hexose concentration. The addition of 16 mM 3-O-methylglucose, which is transported into the beta-cell but not metabolized, produced only a transient 5% increase in beta-cell volume. 4. Exposure of beta-cells to a 15% hypotonic solution resulted in a transient depolarization and electrical activity. Raising the glucose concentration to 20 or 12 mM caused a sustained depolarization and generation of electrical activity. However, the addition of 16 mM 3-O-methylglucose had no effect on beta-cell membrane potential. The glucose-induced increase in volume and induction of electrical activity, when measured in single beta-cells simultaneously, showed comparable kinetics. 5. The secretion of insulin from intact pancreatic islets was stimulated by exposure to hypotonic solutions (10-33% hypotonicity). A 15% hypotonic solution stimulated insulin release to a peak value comparable to that elicited by raising the glucose concentration from 4 to 20 mM. Whereas hypotonic solutions caused a transient stimulation of insulin release, the effect of glucose was sustained. 6. It is suggested that glucose increases the volume in rat pancreatic beta-cells by a mechanism dependent upon metabolism of the sugar. The extent of cell swelling evoked by raised glucose concentrations is sufficient to depolarize the cells and induce electrical and secretory activity and may involve activation of a volume-sensitive anion conductance.

https://physoc.onlinelibrary.wiley.com/doi/pdf/10.1111/j.1469-7793.1997.00191.x

Glucose-induced swelling in rat pancreatic beta-cells.

The whole-cell patch-clamp recording technique was used to measure volume-activated currents in K+-free solutions in RINm5F and HIT-T15 insulinoma cells and in dispersed rat islet cells. Cell swelling, induced by intracellular hypertonicity or extracellular hypotonicity, caused activation of an outwardly rectifying conductance which could be subsequently inactivated by hypertonic extracellular solutions. The conductance required adenosine 5′-triphosphate (ATP) in the pipette solution but was Ca2+ independent. Na+ and Cl− substitution studies suggested that the swelling-activated current is Cl− selective with a halide permeability sequence of Br > Cl > 1. The conductance was reversibly inhibited by the anion channel inhibitors 4,4′-diisothiocyanatostilbene-2,2′-disulphonic acid (DIDS) and by 5-nitro-2-(3-phenylpropylamino) benzoic acid (NPPB). Further evidence for a volume-activated anion conductance was provided by studies of volume regulation in insulin-secreting cells. When RINm5F cells were exposed to a hypotonic medium, the initial cell swelling was followed by a regulatory volume decrease (RVD). This RVD response was also inhibited by DIDS and by NPPB. These data therefore provide evidence for a volume-activated anion conductance in insulin-secreting cells which could be involved in the RVD following osmotic stress. A possible role for the conductance in hypotonically induced insulin release is also discussed.

A volume-activated anion conductance in insulin-secreting cells

Cytotoxic action of methylglyoxal on insulin-secreting cells.

Aldosterone stimulates sodium transport in the inner medullary collecting duct (IMCD) via the classic genomic pathway, but it is not known whether it also acts via a rapid, non-conventional pathway in this part of the nephron. The IMCD regulates the final sodium content of urine and expresses vasopressin receptors coupled to adenylate cyclase. The recently reported rapid, non-genomic actions of aldosterone have been associated mainly with an increase in intracellular Ca(2+); however, it has also been shown to stimulate camp generation. Thus the aim of this study was to determine whether aldosterone stimulates rapid generation of cAMP in isolated IMCD segments. IMCD segments were microdissected from Sprague-Dawley rat kidneys and incubated at 37 degrees C for 4 min with aldosterone (10(-12) to 10(-6) M), vasopressin (10(-12) to 10(-6) M), or a combination of hormones in the presence of a phosphodiesterase inhibitor. cAMP was measured by radioimmunoassay. While corticosterone and dexamethasone were ineffective, aldosterone stimulated a dose-dependent increase in cAMP within 4 min (P<0.05). This action of aldosterone was not inhibited by the MR antagonist spironolactone. Co-incubation of aldosterone with vasopressin resulted in a further increase in cAMP generation above that induced by the neurohypophysial hormone alone. Aldosterone-mediated cAMP generation was not inhibited by a vasopressin V(1) or V(2) receptor antagonist. These data support a novel and rapid, non-genomic effect of aldosterone in IMCD. Aldosterone does not apparently interact with the vasopressin receptor to stimulate cAMP generation.

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Rapid stimulation of cyclic AMP production by aldosterone in rat inner medullary collecting ducts

Measurements were made of trans-sarcolemmal Ca2+ fluxes and intracellular [Ca2+]i in rat ventricular myocytes loaded with Indo-1 to determine how the n-3 polyunsaturated fatty acid eicosapentaenoic acid (EPA) suppresses spontaneous waves of Ca2+ release. We report that in 10 μm EPA, the Ca2+ efflux generated by individual waves increased by 11.3 ± 4.9 % over control levels. However, wave-generated efflux per unit time fell overall by 19 ± 5.3 %. On removal of EPA, wave frequency increased transiently such that Ca2+ efflux was greater than normal and the cell lost 28.0 ± 10.6 μmol l−1 Ca2+. This probably represents the loss of extra Ca2+ accumulated by the sarcoplasmic reticulum (SR), while Ca2+ release was inhibited. These results are evidence of inhibition of the SR Ca2+-release mechanism and reduced availability of Ca2+ to the SR From the relationship between average intracellular Ca2+ and the frequency of spontaneous waves, we have calculated the relative contributions of these different mechanisms to the lower frequency of waves. In EPA, the frequency of spontaneous waves fell by 37.5 ± 8.1 %, the majority of this (29.2 ± 8.8 %) is due to inhibition of the Ca2+-release mechanism. In EPA, the rate of fall of Ca2+ in the caffeine response (an indicator of surface membrane Ca2+ efflux pathway activity) was not altered. We conclude, therefore, that the lower resting level of Ca2+ observed in EPA is due to a lower influx of Ca2+ across the surface membrane rather than increased activation of efflux pathways. How these effects might contribute to the anti-arrhythmic actions of EPA is discussed.

E. A. Sheader

Papers

Glucose-induced swelling in rat pancreatic beta-cells.

A volume-activated anion conductance in insulin-secreting cells

Cytotoxic action of methylglyoxal on insulin-secreting cells.

Rapid stimulation of cyclic AMP production by aldosterone in rat inner medullary collecting ducts

Direct and indirect modulation of rat cardiac sarcoplasmic reticulum function by n-3 polyunsaturated fatty acids.