Regulation of neuronal cell volume: from activation to inhibition to degeneration.

Since the emergence of single-celled protozoans, animals have survived and flourished in the face of frequent changes in the composition of their internal and external environments. Among the common challenges to survival is the disturbance of cell volume homeostasis. Despite the fact that evolution has endowed mammals with complex systems to regulate water and solute balance, significant deviations of the cell volume regulatory ‘set-point’ can still occur. One need only consider fundamental cellular processes such as endo- and exocytosis to appreciate that cell volume changes are often a normal part of cellular function. Conditions such as energy depletion, hypoxia/ischaemia and acidosis cause cells to accumulate water and swell. During the progression of apoptosis, cells initially lose water and shrink, and then they swell before dying. Neurons are perhaps more vulnerable than other cells to changes in volume. This is because ionic gradients across the plasma membrane are critical for establishing both the osmotic distribution of water and normal electrical excitability. Changes of intracellular volume as neurons swell and shrink produce corresponding changes in the concentration of ions and other signalling molecules. Because the brain is housed in a rigid cranium, swelling and shrinking of cells will change the extracellular fluid volume and thus the spatial relationship between neurons and adjacent cell types, affecting both the concentration and diffusion kinetics of synaptically released neurotransmitters. Fortunately, neurons (like most somatic cells) have developed complex mechanisms to actively defend their volume. When they swell, for example by exposure to extracellular hypotonicity, neurons undergo a volume regulatory decrease (VRD) in solute content. Within seconds to minutes they begin to extrude inorganic ions (mostly K+ and Cl−) through a variety of membrane channels and transporters. This lowers intracellular osmolality, favours osmotic loss of water, and thereby restores volume toward normal. The initial loss of ions is usually followed within hours by loss of intracellular organic solutes. These are mostly in the form of amino acids (glutamine, glutamate, taurine, etc.), inositol, creatine, etc. The converse occurs when neurons shrink, for example by exposure to extracellular hypertonicity. They undergo a volume regulatory increase (VRI) in solute content characterized by an initial influx of ions (mostly Na+ and Cl−) followed by transporter mediated uptake of organic osmolytes. The resulting increase of intracellular osmolality leads to osmotic influx of water, again restoring volume toward normal. Studies have demonstrated the robustness of neuronal volume defence and have shown that osmo-adaptive VRD and VRI mechanisms produce a state of allostasis (i.e. maintaining stability through change) in which neuronal behaviour is remarkably well preserved (Verbalis, 2010). Understanding factors that enable maintenance of neuronal function under volume adapted conditions has the potential to provide new information that could aid the design of new and improved therapeutics for stroke, neurodegenerative diseases (Alzheimer's, Parkinson's, Huntington's) as well as hyperexcitability (elilepsy, hyperalgesia, dysautonomias, etc.) and hypoexcitability (paresthesia, dysautonomias, etc.) disorders. To explore this thesis, the Journal of Physiology sponsored a symposium entitled Regulation of Neuronal Cell Volume: From Activation to Inhibition to Degeneration, held at the 2010 Experimental Biology meeting. The symposium was well attended by a scientifically diverse audience. The symposium began with Florian Lang (University of Tubingen, Germany) discussing functions of the ubiquitously expressed enzyme serum- and glucocorticoid-inducible kinase-1 (SGK1) in brain. He emphasized that the SGK1 gene is cell volume regulated such that expression increases rapidly in response to osmotically obligated water loss and isotonic cell shrinkage. Indeed, cell volume sensitivity of SGK1 transcription may well represent an early trigger of osmo-adaptive responses in the dehydrated brain (Lang et al. 2010). Although SGK1 is not unique in being transcriptionally regulated by dehydration, the fact that its activity leads to expression of an array of ion channels and transporters that contribute to cell volume defense (RVD and RVI) underscores the overall thesis of the symposium. Next, Daniel Foster (University of Michigan, USA), substituting for Stephen Fisher, addressed the exciting question of how osmolyte homeostasis in neurons is regulated by activation of membrane receptors. He discussed recent evidence that G-protein coupled receptor (GPCR) activation during hypoosmotic swelling permits neurons to more efficiently respond to small, physiologically relevant reductions of osmolality (Fisher et al. 2010). GPCR-mediated amplification of VRD mechanisms has important clinical implications since, as noted above, neuronal swelling is a key feature of neurodegenerative diseases, hyponatraemia, stroke, acidosis, etc. Eric Delpire (Vanderbilt University, USA) then discussed new evidence that brought together the concepts of early transcriptional activation in volume disturbed neurons (Lang et al. 2010) with amplification of osmo-adaptive responses by GPCRs (Fisher et al. 2010). He presented evidence that a key membrane transporter, the Na+ −K+ −2Cl− cotransporter (NKCC), which can be induced by SGK1 activity, is activated in an additive fashion by the sterile-20 kinases SPAK and OSR1. He showed convincing evidence that intracellular Cl− accumulation in dorsal root ganglion (DRG) neurons by kinase activation of NKCC promotes primary afferent depolarization, thereby interfering with sensory (pain) transmission to the spinal cord (Delpire & Austin, 2010). Finally, Glenn Toney (University of Texas Health Science Center at San Antonio, USA) discussed known features of CNS circuitry that support elevated sympathetic nerve activity in response to serum hyperosmolality/hypernatraemia. Gaps in our understanding of osmosensory transduction by intrinsically osmosensitive neurons of the ventral forebrain were identified. He speculated on possible mechanisms by drawing on information from osmosensitive neurosecretory neurons that release of vasopressin from the posterior pituitary (Bourque, 2008). The importance of understanding neuronal osmosensory transduction was underscored by evidence that osmotic activation of sympathetic nerve discharge could contribute significantly to the pathogenesis of salt-sensitive cardiovascular diseases, including hypertension and heart failure (Toney & Stocker, 2010). In summary, Regulation of Neuronal Cell Volume: From Activation to Inhibition to Degeneration provided a review of essential information and new evidence about how cell volume defence governs neuronal function. Because cell volume defence appeared early in animal evolution, the symposium perhaps most provocatively emphasized the concept that osmo-adaptive volume regulatory mechanisms could represent a molecular foundation upon which higher order functions of the CNS were built.