Review
Roles of cell volume in molecular and cellular biology

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Abstract

Extracellular tonicity and volume regulation control a great number of molecular and cellular functions including: cell proliferation, apoptosis, migration, hormone and neuromediator release, gene expression, ion channel and transporter activity and metabolism. The aim of this review is to describe these effects and to determine if they are direct or are secondarily the result of the activity of second messengers.

Introduction

The cell volume and its regulation play a role in a great number of molecular and cellular functions (Fig. 1). Beyond the change in extracellular osmolarity, the cell volume is dependent on several parameters including the activity of ion channels and transporters (Wehner et al., 2003). Among these parameters the acute and chronic fluxes of monovalent ions (thick line in Fig. 1) are important regulators of cell volume, which in turn control several molecular and cellular functions. From this point of view, the activity of K+ and Cl channels are, in relationship with other ions and molecules including ATP and Ca2+, a key feature of cell biology. For this reason, we have developed a new hypothesis based on many observations that cell volume controlled by ion fluxes is responsible for several molecular and cellular functions through membrane tension, concentration of several messengers and macromolecular crowding, i.e. the relative concentration of intracellular molecules (Rouzaire-Dubois et al., 2004, Rouzaire-Dubois et al., 2009). In this review we describe the roles of cell volume in molecular and cell biology and in each case we try to propose a physico-chemical interpretation of these roles.

Section snippets

Proliferation

During the cell cycle, cells must double their volume so that daughter cells have the same size that the mother cell. In the 1970’s, (Cone, 1971) and (Cone and Cone, 1976) proposed a “unified theory” suggesting that intracellular Na+ level was of major mitogenic importance. They showed that, in differentiated neurons from the central nervous system of chick embryo spinal cord, DNA synthesis and mitosis were induced by depolarization with different agents that produce a rise in the intracellular

Apoptosis

Programmed cell death or apoptosis is important in tissue maintenance to compensate for cell proliferation by cell death. Apoptosis is characterised by DNA fragmentation, mitochondrial damage and apoptotic volume decrease (AVD) that result in minimal inflammation to the surrounding tissue. In vitro, apoptosis can be induced by staurosporine that induces a rapid AVD. This cell shrinkage is due to a Cl, K+ and osmotically obliged water efflux inducing a cytoplasmic condensation.

Recently, Ernest

Migration

Cells that present an aberrant migration, notably cancer cells, have the ability to modulate their volume and shape to move through the extracellular spaces. This property has been very well studied on gliomas that are the most deadly cancers. Recent studies on glioma cells in isotonic conditions showed that the changes in cell volume and shape involved the secretion of Cl and K+ ions triggered by an increase in intracellular Ca2+ (Wondergem et al., 2008) in association with water movements

Hormone and neuromediator release

In various cell types including endocrine cells, neurons, leucocytes and exocrine pancreatic cells, cell swelling induced by an hyposmotic stress or by an isosmolar medium containing permeant molecules such as ethanol or urea causes an immediate release of peptide hormones and enzymes (for review see Strbak and Greer, 2000).

During cell swelling, the secretion of tyrosine releasing hormone, oxytocine, prolactine and insulin was not depressed by inhibition of stretch-activated channels,

Gene expression

In mammalian kidney, the extracellular tonicity varies widely due to the accumulation of NaCl. In order to avoid excessive cell shrinkage and apoptosis, the tonicity-responsive enhancer binding protein (TonEBP) regulates transcription of tonicity-responsive genes (see review by Jeon et al., 2006). Under hypertonicity the osmotic gradient across the plasma membrane is maintained constant by the accumulation of compatible osmolytes such as myo-inositol, betaine, sorbitol, taurine, and

Activation of ion channel and transporters activity

For several decades, it has been known that animal cells regulate precisely their volume (Tosteson and Hoffman, 1960). Following anisotonic challenges are changes in ion transport, and the cell volume increases or decreases. Generally, these volume changes are compensated by regulatory volume decrease (RVD) or increase (RVI) mediated by transport of ions through volume-activated transporters or channels (reviewed by Sarkadi and Parker, 1991) and osmotically obliged water fluxes through

Metabolism

Anisosmolarity influences the cell volume and metabolic activities (Dubyak, 2004, Wehner et al., 2003). In recent years, it has become evident that the cell volume is an important factor in defining the regulation of cell metabolism. Astrocyte swelling was shown to stimulate glycogen synthesis (Dombro et al., 2000). Thus further acting as a signal for proliferation and playing a role in gliosis. In glioma cells, osmolarity affects the intracellular nucleoside triphosphate level, rate of fatty

Conclusion

Modulations of cell volume and shape are involved in several cellular functions. They are due to changes in K+ and Cl fluxes often triggered by either an increase or a decrease in intracellular Ca2+ concentration. These properties are involved in several pathologies including renal failure, anaemia, myasthenia and cancer where the balance between cell proliferation and cell death is modified. What is more, cancer cells have the faculty to change their volume and shape so that they diffuse into

Acknowledgements

We thank Dr. Seana O’Regan for helpful comments on the manuscript.

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