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Edited by Christopher D. Verrico
Nominated by Olaf Andersen
Editor, Journal of General Physiology
Cornell University
sparre{at}med.cornell.edu
Question: How does the transient receptor potential vanilloid 1 (TRPV1) variant relay gustatory responses to ethanol? Can this same variant account for amiloride-insensitive NaCl gustatory physiology?
Background: Individual taste buds contain scores of taste receptor cells (TRCs) that synapse with chorda tympani (CT) neurons and ultimately determine palatability. TRCs express a variety of different proteins, including two sodium-permeable channels located on the apical membrane: the amiloride-sensitive sodium channel, which is activated by NaCl and is responsible for the perception of salt taste, and the amiloride-insensitive TRPV1-variant sodium channel, which is a nociceptor activated by capsaicin (CAP), acid, and heat. In addition to producing gustatory responses, ethanol modulates TRPV1 variant responses; however, the mechanism(s) by which ethanol affects these responses is unknown.
Observations: Using various in vitro and in vivo paradigms, Lyall et al. demonstrate that a TRPV1 variant (TRPV1t), which is dissimilar from other TRPV1 variants because it is not activated by acid, is responsible for the amiloride-insensitive salt taste. Moreover, pharmacological and genetic manipulations were used to demonstrate that although ethanol does not affect TRPV1t temperature threshold it does potentiate the taste sensitivity of TRPV1t by modulating taste cell volume in TRCs and evoking phasic and/or tonic responses in rat CT neurons.
Significance: The TRPV1t variant was identified as the distinct amiloride-insensitive pathway that relays gustatory information concerning NaCl. Additionally, although the evoked phasic/tonic responses of CT neurons in response to ethanol have been known, the physiology of these responses were unknown until Lyall et al. determined that they are TRPV1t dependent and vary according to flow rates, temperature, and the ionic composition of the experimental medium. It is noteworthy that ethanol alone produced responses in taste cells and CT neurons and affected TRC volume at 3.43 M (20% vol/vol) because ethanol is frequently used as a vehicle on cell preparations. Thus care must be taken when interpreting results using ethanol as a vehicle in certain cells.
From a Journal of Physiology themed issue on "How do environmental influences permanently affect the developing fetus and neonate?"
Nominated by Geraldine Clough
Senior Editor, Journal of Physiology
School of Medicine, University of Southampton
g.f.clough{at}soton.ack.uk
Question: Do perturbations of the maternal cardiovascular system during gestation and/or lactation produce cardiovascular abnormalities in offspring?
Background: Accumulating evidence supports the fetal-programming theory, which posits that a developing fetus responds to environmental perturbations by diverting resources to compensate for maternal deficiencies. These compensatory mechanisms appear to differentially affect the genders and have long-term sequelae, including structural changes to organs. In fact, the long-term consequences may be long indeed, extending across generations. The susceptibility of an organ to fetal programming likely depends on the rate at which its cells divide. Thus the developing cardiovascular system could be particularly susceptible to perturbations of the placental milieu because it is almost fully developed by midgestation, with cardiomyocytes rarely replicating after birth. This is supported by observations in humans and animals where maternal nutrient deficiencies and excesses during pregnancy are reported to profoundly affect fetal cardiovascular formations.
Observations: Several recent manuscripts appearing in The Journal of Physiology further describe the consequences of maternal cardiovascular perturbations on offspring. Armitage et al. found that the previously reported cardiovascular developmental programming of first-generation (F1) rat offspring from dams fed an animal-fat-rich diet, which results in a phenotype characteristic of metabolic syndrome, is associated with alterations in aortic structure and function. Some mechanistic data is also provided and suggests that altered renal enzyme activity contributes to the induced hypertension of offspring. In contrast to Armitage et al., Zambrano and colleagues examined cardiovascular function in second-generation (F2) rat offspring of grandmothers administered a low-protein (LP) diet during pregnancy and/or lactation, which resulted in four F1 offspring groups: control diets during pregnancy and lactation (C/C), LP diets during pregnancy and lactation (LP/LP), LP diet only during pregnancy (LP/C), and LP diet only during lactation (C/LP). F2 offspring of LP/C and C/LP F1 mothers were more susceptible to insulin resistance than C/C offspring. Interestingly, this effect was gender specific; it was more pronounced for F2 females of LP/C grandmothers and F2 males of C/LP grandmothers. Gender-specific cardiovascular perturbations are also reported by Bae et al., who used an entirely different paradigm to affect maternal cardiovascular physiology. F1 males prenatally exposed to cocaine were more susceptible to increased ischemia and reperfusion (I/R) injury than females. Moreover, the cardiovascular dysfunctions in F1 offspring were associated with a decrease in the downstream messenger PKC-
, which plays an important role in protecting against I/R injury.
Significance: These studies support the hypothesis that an adverse environment in utero and/or during lactation can adversely influence generations of offspring via fetal programming, which leads to cardiovascular malformations. These findings may have important implications for congenital cardiovascular malformations as they remain a major public health problem, accounting for a large proportion of the infant mortality rate. This is particularly important because, notwithstanding advancements in surgical techniques, postnatal attempts to reverse the consequences of congenital cardiovascular malformations can produce their own untoward repercussions. These studies, together with future studies, will help to provide guidelines for maternal behaviors that will lead to ideal placental/lactation conditions for the optimal well being of their offspring.
Nominated by Anthony (Tony) P. Farrell
University of British Columbia
farrellt{at}interchange.ubc.ca
Question: What underlies the rapid increase in ventricular mass in postprandial pythons?
Background: The physiological phenomenon of ventricular hypertrophy occurs in response to increased stress, such as exercise, that can result in increased stroke volume and subsequently decreased heart rates; however, the response can also be pathological as observed in hypertensive heart disease. Nonmammalian vertebrates such as the Burmese python can be an ideal model for exploring extreme physiological upregulation of cardiac tissue, because during the digestive process python metabolic rates increase up to 40 times over basal levels for up to 2 wk. This is accompanied by a significant increase in the wet mass of several organs, including the heart. However, the mechanisms underlying this remarkable hypertrophy were previously unresolved.
Observations: Oxygen consumption was found to increase sevenfold while ventricular mass rapidly increased by 40% after only 48 h into the digestive period of pythons. The rapid cardiac remodeling was transient, persisting only during digestion when metabolic rate was elevated. Several independent measures implicated cellular hypertrophy as the causal factor of the rapid 40% increase in ventricular mass. Confirmation of this hypothesis comes from the demonstration that there was a concurrent upregulation of heavy-chain cardiac myosin mRNA expression.
Significance: Andersen et al. demonstrate the remarkable ability of the python heart to rapidly synthesize substantial amounts of fresh heart muscle in response to feeding and concurrent with a large increase in metabolic rate. The ventricular hypertrophy observed in pythons makes an attractive experimental preparation to investigate cardiac hypertrophy in other animals and to explore its underlying mechanisms because of its rapid onset and the ease with which it can be produced when compared with mammalian models.
B ligand (RANKL) on the calcium/calcineurin/NFAT pathway in osteoclasts. Komarova SV, Pereverzev A, Shum JW, Sims SM, and Dixon SJ. Proc Natl Acad Sci USA 102: 2643–2648, 2005.
Nominated by Heini Murer
Physiologisches Institut
hmurer{at}access.unizh.ch
Question: What is the mechanism of acidosis-induced stimulation of osteoclast resorptive activity?
Background: Physiological pH is maintained predominately by compensatory mechanisms between the kidneys (HCO3– production) and lungs (CO2 production). When homeostatic conditions are perturbed and there is an excessive accumulation of acid in the body, acidosis results. Acidification stimulates the lysis and assimilation (resorption) of minerals by osteoclasts to counteract acidosis and has been shown to upregulate the expression of the cytokine receptor activator of NF-B ligand (RANKL). RANKL stimulates the formation and resorptive activity of osteoclasts via activation of phospholipase C (PLC) and by subsequently increasing intracellular Ca2+ ([Ca2+]i). This in turn stimulates the phosphotase calcineurin, permitting the translocation of nuclear factor of activated T cells (NFAT) to nuclei, which is essential for osteoclastogenesis. This pathway could potentially mediate the acidosis-induced resorptive activity of osteoclasts via the RANKL receptor, but until now there was no supporting evidence for this hypothesis.
Observations: Komarova and colleagues made a number of important observations regarding the mechanism by which acidification leads to the osteoclasts’ resorptive activity. Similar to RANKL-induced resorptive activity in osteoclasts, reducing extracellular pH resulted in the accumulation of the osteoclastogenic transcription factor NFATc1 in nuclei, which involved a transient PLC-dependent increase in [Ca2+]i and calcineurin. In contrast to RANKL, pH-induced resorptive activity also involved suppression of NFATc1 inactivation and was found to possess a distinct mechanism to maintain NFATc1 nuclear localization. Finally, osteoclasts were found to express a proton-sensing G protein-coupled receptor (GPCR) that couples extracellular acidification to increased [Ca2+]i.
Significance: In addition to delineating a mechanism by which acidosis induces resorptive activity in osteoclasts, Komarava et al. provide a possible candidate GPCR for mediating this process. The significance of understanding acidosis-induced osteoclast activation is underscored by its putative involvement in the pathogenesis of rheumatoid arthritis, periodontitis, and bone metastases. As such, these findings may potentially provide novel therapeutic targets to mitigate systemic acidification and thus osteoclast activation.
Nominated by Lawrence Palmer
Associate Editor, Journal of General Physiology
Cornell University
lgpalm{at}med.cornell.edu
Question: Can an innovative technique be developed to examine lung physiology while preserving dynamic functions/interactions?
Background: The primary function of the lungs, which are ~10% solid tissue (the remainder is filled with air and blood), is to facilitate rapid gas (O2/CO2) exchange. This occurs in the millions of the highly branched alveoli where blood and inspired air are separated by only a thin layer of tissue. Thus functionally the lungs can be divided into the conducting airways for ventilation and the circulatory gas-exchange units for perfusion. Regulation of ventilation and perfusion is determined by the diameter of the smooth muscle cells (SMCs) that line these conduits. Specific physiological details of this regulatory system, however, have been difficult to elucidate, because experimental preparations used to date, although important, have been problematic. For example, the use of thick tissue slices does not preserve vascular spaces; isolated tissue samples are devoid of neural inputs and surrounding tissues; and imaging techniques only use single-cell preparations.
Observations: Perez and Sanderson describe a thin multicellular lung-slice preparation that preserves parenchymal vascular spaces and adjacent cell types. Differential perfusion of the arterial system and airspaces allowed them to cut slices of lung tissue thin enough to be optically imaged, which provided them with the ability to study Ca2+ oscillations in SMCs. Using this innovative approach, they describe how bronchiolar and pulmonary arterial muscle contractions are regulated via Ca2+ oscillations.
Significance: The role of bronchiolar and arteriolar Ca2+ signaling in SMC contractions is an interesting finding alone. However, the major contribution from these studies is an empirical approach that allows preservation of physiological interactions while studying lung physiology. Thus, because infections occur more frequently in the respiratory tract than in any other organ, future studies using this novel approach may help in elucidating the defects that underlie the pathophysiology of diseases such as asthma as well as understanding normal lung physiology.
Nominated by Pontus Persson
Editor, American Journal of Physiology-Regulatory,
Integrative, and Comparative Physiology
Humboldt University
pontus.persson{at}charite.de
Question: Does suppression of motor activity influence the concomitant changes in feeding behaviors following oleoylethanolamide (OEA) exposure?
Background: A lipid synthesized in the central nervous system and small intestine, OEA is implicated in maintaining energy balance. Recent reports suggest that OEA induces anorexia and decreases the rate of body weight gain, potentially by stimulating lipolysis, delaying meal onset, and reducing meal size. These effects are absent when OEA is administered centrally or in the peroxisome proliferator-activated receptor-
(PPAR-) knockout, a ligand-activated transcription factor. OEA also activates the nonselective cation channel transient receptor potential vanilloid type 1 (TRPV1). Similar to PPAR-, TRPV1 is found in various brain areas, including regions associated with motor activity. Thus OEA-induced TRPV1 or PPAR- activation could mediate the OEA-induced decrease in locomotor activity, effects that might contribute to the anorexigenic properties of OEA.
Observations: Using several distinct paradigms, Proulx et al. determined that the OEA-induced reduction in feeding behavior is not due to nonspecific behavioral effects, visceral illness, or aversion in rodents. Surprisingly, under these experimental conditions OEA did not increase energy expenditure or alter plasma levels of several other gut hormones involved in food intake. OEA did, however, produce reductions in locomotor activity, which was similar to those observed following TRPV1 and PPAR- agonist administration. Nonetheless, the OEA-induced anorexia is unlikely due to impaired locomotor activity.
Significance: These results, coupled with previous reports, suggest that OEA’s antiobesity properties are a result of a peripherally induced increase in lipid metabolism. However, further empirical analysis at the preclinical level will be required before the therapeutic potential of OEA can be resolved. Nonetheless, these results suggest that OEA-like compounds that interact with the PPAR- pathway may prove useful as pharmaceutical targets for eating disorders.
Nominated by Ulrich Pohl
Ludwig-Maximilians-Universitat Munchen
upohl{at}lmu.de
Question: What is the physiological significance of the adipocytokines preferentially secreted by visceral fat?
Background: Adipose tissue can be subdivided into visceral (i.e., intra-abdominal) and subcutaneous fat. Interestingly, visceral fat has been positively correlated with a wide range of health indicators, including cholesterol, triacylglycerols, and insulin. Predictably, therefore, the proportion of visceral fat in an individual may relate to different risk factors for obesity, type 2 diabetes, and cardiovascular diseases. In fact, one of the factors that best correlates obesity with metabolic syndrome is the distribution of adipose tissue in the abdominal region. Recently, adipose tissue has been shown to possess endocrine properties that are responsive to physiological signals, resulting in the secretion of adipocytokines, which have important functions in metabolic homeostasis.
Observations: Samples of human subcutaneous and visceral fat were analyzed and determined to differentially express the putative adipocytokine pre-B cell colony-enhancing factor (PBEF). Given the disproportionate abundance of PBEF in visceral fat, Fukuhara et al. redesignated it as "visfatin." Subsequently, plasma visfatin concentrations were analyzed and correlated with fat deposits in humans and mouse models of obesity. Visfatin was strongly correlated with visceral fat levels, but not subcutaneous levels. Moreover, the physiological role of visfatin was determined; it displayed insulin-mimetic properties and lowered plasma glucose levels in a mouse model of type 2 diabetes as well as in insulin-resistant and insulin-deficient mice. Moreover, visfatin bound to the insulin receptor in a noncompetitive manner, suggestive of a distinct binding site.
Significance: Certainly, future research efforts will be aimed at delineating the role of visfatin in the pathogenesis of obesity, diabetes, and metabolic syndrome. Additionally, the unique interaction of visfatin with the insulin receptor may represent a significant contribution providing novel approaches to elucidate aspects of insulin-related physiology and potentially antidiabetic pharmacotherapies.
Nominated by Ulrich Pohl
Ludwig-Maximilians-Universitat Munchen
upohl{at}lmu.de
Question: Are microRNAs (miRNAs) responsible for cell/organ-type-specific gene-expression profiles?
Background: Among the most minuscule entities in the human genome are miRNAs: 17- or 20-nucleotide-long, noncoding RNA fragments that posttranscriptionally suppress gene expression. Small interfering RNA (siRNA) is a new and powerful technique that provides a simple mechanism to manipulate gene activity. Off-target effects of siRNAs have been observed on microarrays, and postulating that the off-target effects of siRNAs are due to miRNA-mimetic activity, Lim et al. used microarray analysis to detect changes in gene expression associated with miRNAs.
Observations: Microarray analyses of mRNAs expressed in human cells revealed the abilities of two miRNAs, miR-124 and miR-1, to downregulate 174 and 96 genes, respectively. Strikingly, by downregulating these genes, miR-124 and miR-1 made the expression profile of the transfected cells more like that of the native tissues of the miRNA, i.e. brain for miR-124 and muscle for miR-1. Several lines of evidence suggest that the shifts in gene expression are a result of the miRNA interacting directly with the 3' untranslated regions (UTRs) of the downregulated transcripts, which highlights the importance of the miRNA’s 5' end or "seed" region.
Significance: The ability to detect reductions in gene expression in vitro that correspond to the in vivo expression specificities of miRNAs is remarkable. Even more titillating is the idea that miRNAs appear to define and maintain different cell types by downregulating a previously unappreciated number of targets, which has far-reaching implications for animal development and physiology.
Nominated by Jeff Sands
Editor, American Journal of Physiology, Renal
Physiology
Emory University
jsands{at}emory.edu
Question: What mechanism underlies the renoprotection provided by mesenchymal stem cell (MSC) administration following acute renal failure (ARF)?
Background: ARF is characterized by an inability of the kidneys to excrete wastes, concentrate urine, and conserve electrolytes. Ischemia/reperfusion (I/R)-induced ARF results from a decrease in the renal blood supply, leading to tissue hypoxia, which subsequently causes a complex cascade of events resulting in renal injury. A number of processes have been implicated in the pathogenesis of hypoxia-induced cell injury, including disturbances of vascular function, cellular metabolism, and free-radical production. Thus the mechanisms underlying I/R-induced damage to kidneys are likely multifaceted and reciprocal, involving hypoxia, inflammation, and vascular dysfunction. Although stem cell therapy has been demonstrated as being efficacious, the mechanism of this phenomenon is unclear.
Observations: Intracarotid administration of multipotent MSC to rats with ARF improved prognosis by mitigating the I/R-induced inflammatory, vascular, and apoptotic/necrotic sequelae. This prophylactic effect was evident as early as 24 h after MSC infusion, which suggests that it was not due to transdifferentiation of the MSCs into tubular or endothelial cell phenotypes but resulted from paracrine effects. This was supported by the demonstration that MSCs attenuated the expression of proinflammatory and upregulated expression of anti-inflammatory cytokines.
Significance: Using both in vitro and in vivo techniques, Togel et al. demonstrate the therapeutic potential of MSCs to protect against I/R-induced ARF. The sagacious experimental design employed allows for some discernment to be made into the controversial mechanism by which MSCs produce renoprotection. Given the high frequency, multiple causes, resistance to traditional therapies, and significant morbidity of ARF, MSC administration may represent a logical clinical approach to ameliorate ARF.
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