Yeast osmoregulation - glycerol still in pole position.

In response to osmotic dehydration cells sense, signal, alter gene expression, and metabolically counterbalance osmotic differences. The main compatible solute/osmolyte that accumulates in yeast cells is glycerol, which is produced from the glycolytic intermediate dihydroxyacetone phosphate. This review covers recent advancements in understanding mechanisms involved in sensing, signaling, cell-cycle delays, transcriptional responses as well as post-translational modifications on key proteins in osmoregulation. The protein kinase Hog1 is a key-player in many of these events, however, there is also a growing body of evidence for important Hog1-independent mechanisms playing vital roles. Several missing links in our understanding of osmoregulation will be discussed and future avenues for research proposed. The review highlights that this rather simple experimental system-salt/sorbitol and yeast-has developed into an enormously potent model system unravelling important fundamental aspects in biology.

Volume sensing in the transient receptor potential vanilloid 4 ion channel is cell type-specific and mediated by an N-terminal volume-sensing domain.

Many retinal diseases are associated with pathological cell swelling, but the underlying etiology remains to be established. A key component of the volume-sensitive machinery, the transient receptor potential vanilloid 4 (TRPV4) ion channel, may represent a sensor and transducer of cell swelling, but the molecular link between the swelling and TRPV4 activation is unresolved. Here, our results from experiments using electrophysiology, cell volumetric measurements, and fluorescence imaging conducted in murine retinal cells and Xenopus oocytes indicated that cell swelling in the physiological range activated TRPV4 in Müller glia and Xenopus oocytes, but required phospholipase A2 (PLA2) activity exclusively in Müller cells. Volume-dependent TRPV4 gating was independent of cytoskeletal rearrangements and phosphorylation. Our findings also revealed that TRPV4-mediated transduction of volume changes is dependent by its N terminus, more specifically by its distal-most part. We conclude that the volume sensitivity and function of TRPV4 in situ depend critically on its functional and cell type-specific interactions.

TRPing on Cell Swelling - TRPV4 Senses It.

The transient receptor potential vanilloid 4 channel (TRPV4) is a non-selective cation channel that is widely expressed and activated by a range of stimuli. Amongst these stimuli, changes in cell volume feature as a prominent regulator of TRPV4 activity with cell swelling leading to channel activation. In experimental settings based on abrupt introduction of large osmotic gradients, TRPV4 activation requires co-expression of an aquaporin (AQP) to facilitate such cell swelling. However, TRPV4 readily responds to cell volume increase irrespectively of the molecular mechanism underlying the cell swelling and can, as such, be considered a sensor of increased cell volume. In this review, we will discuss the proposed events underlying the molecular coupling from cell swelling to channel activation and present the evidence of direct versus indirect swelling-activation of TRPV4. With this summary of the current knowledge of TRPV4 and its ability to sense cell volume changes, we hope to stimulate further experimental efforts in this area of research to clarify TRPV4's role in physiology and pathophysiology.

Sensing and regulation of cell volume - we know so much and yet understand so little: TRPV4 as a sensor of volume changes but possibly without a volume-regulatory role?

Cellular volume changes lead to initiation of cell volume regulatory events, the molecular identity of which remains unresolved. We here discuss experimental challenges associated with investigation of volume regulation during application of large, non-physiological osmotic gradients. The TRPV4 ion channel responds to volume increase irrespectively of the molecular mechanism underlying cell swelling, and is thus considered a sensor of volume changes. Evidence pointing towards the involvement of TRPV4 in subsequent volume regulatory mechanisms is intriguing, yet far from conclusive. We here present an experimental setting with astrocytic cell swelling in the absence of externally applied osmotic gradients, and the lack of evidence for involvement of TRPV4 in this regulatory volume response. Our aim with these new data and the preceding discussion is to stimulate further experimental effort in this area of research to clarify the role of TRPV4 and other channels and transporters in regulatory volume responses.