HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via Google Scholar Google Scholar Search for Related Content

Highlights From The Literature

Edited by Christopher D. Verrico

Nominated by Olaf Andersen
Editor, Journal of General Physiology
Cornell University
sparre{at}med.cornell.edu

Question: Does stretch activation contribute to ventricular force in cardiac tissue?

Background: In the heart, the left ventricle forces oxygenated blood into the arteries. The blood then returns to the right atrium and passes down to the right ventricle. The right ventricle pumps the blood to the lungs, and then the blood returns to the left atrium where it is passed into the left ventricle. Recent evidence suggests that when the left ventricle stretches it causes a multiphase force response, including a delayed development of force, or stretch activation, which powers the ejection of the blood. However, the mechanism underlying the activation of this stretch-activation phenomenon in myocardium is unknown.

Observations: Stelzer et al. found that stretch activation could be induced in mouse myocardium and that there was a mulitphasic force response to the stretch. Initially, force increased in proportion to the stretch, declined, and then redeveloped to a new steady level, which represents the delayed force characteristics of stretch activation. The amplitude and rate of stretch activation varied with the degree of activation, levels of Ca²⁺, and cooperative binding of cross bridges to thin filaments.

Significance: The stretch-activation response was first described as the essential generation of oscillatory power required for the beating of insect wings. Now, the roles of stretch activation, Ca²⁺, and strong binding of cross bridges to cardiac muscle force generation are delineated. Thus this intrinsic force-regulating mechanism might contribute to increased systolic ejection in response to Ca²⁺ during ventricular ejection.

Nominated by Kim Barrett
Associate Editor, Journal of Physiology
University of California, San Diego
kbarrett{at}ucsd.edu

Question: Does the kinase, WNK3, play a role in renal NaCl and K⁺ homeostasis?

Background: Nephrons, the basic functional units of the kidney, eliminate wastes from the body, regulate blood pH, volume, and pressure, and control levels of electrolytes and metabolites. Within the nephron, NaCl reabsorption is mediated by a Na-Cl cotransporter (NCC) in the distal convoluted tubule (DCT) and early connecting tubule (CNT), whereas Na⁺ reabsorption is mediated by the epithelial Na⁺ channel (ENaC) in the collecting duct (CD) and late CNT. This latter process also provides the driving force for K⁺ secretion via the ROMK1 K⁺ channel. However, it is not entirely clear how the NaCl and K⁺ pathways are independently regulated to maintain homeostasis.

Observations: Leng et al. determined that WNK3, which is a kinase known to regulate multiple ion transporters including NCC, is expressed in CD principal cells. In addition, WNK3 specifically inhibited ROMK1 activity by modulating its expression on the cell membrane. The mechanism by which WNK3 affected ROMK1 activity was in a noncatalytic manner, which is in contrast to the catalytic-dependent manner by which it activates NCC.

Significance: These data, along with the known regulatory activity of WNK3 on the NCC, suggest that WNK3 is a physiologically relevant component of the regulatory pathway that balances renal NaCl reabsorption and K⁺ secretion. Thus the members of the WNK family (WNK1, WNK3, and WNK4) are likely differentially recruited to execute specific responses to changing but specific physiological conditions. Because of its potential importance in nephron regulation, WNK3 may represent a novel target for drugs to treat high blood pressure and edema.

Nominated by Jerry Dempsey
Editor, Journal of Applied Physiology
University of Wisconsin
jdempsey{at}wisc.edu

Question: Is the hypertension observed in patients with obstructive sleep apnea (OSA) caused by hypoxia-induced sympathetic activation?

Background: OSA is caused by muscle relaxation, which collapses the airway, stops breathing, and awakens the sleeper to open the airway. OSA is common in obesity and both are associated with an increase in sympathetic/noradrenergic activity, which has adverse consequences on the cardiovascular system. Continuous positive airway pressure (CPAP) is a treatment for OSA that reduces norepinephrine (NE) levels and mitigates cardiovascular complications. However, whether CPAP reduces NE levels by affecting release and/or clearance rate and the impact of these effects on blood pressure are unknown.

Observations: Mills et al. studied the effects of CPAP and oxygen supplementation, an alternative treatment for OSA, on NE kinetics and cardiovascular responses in obese patients. CPAP increased NE clearance but did not affect NE release, whereas supplemental oxygen had no effect on either measure. In addition, CPAP, but not oxygen supplementation, reduced blood pressure and heart rate.

Significance: Obstructive sleep apnea is a serious health disorder that contributes to cardiovascular complications, decreased work productivity, automobile accidents, and death. Previously, the mechanism by which OSA causes hypertension was proposed to result from hypoxia-induced sympathetic activation. However, the results reported by Mills et al. suggest that apneic episodes are of greater importance than hypoxia in determining sympathetic activation and the associated hypertension.

Nominated by Litsa Kranias
University of Cincinnati Medical College
litsa.kranias{at}uc.edu

Question: What is the molecular mechanism by which 17ß-estradiol (E₂) affects ERK signaling in cerebellar neuronal cultures? Is this preserved in vivo?

Background: Estrogens mediate many of their effects via the intracellular estrogen receptors (ERs) ER and ERß. Estrogens also induce rapid signaling via a variety of signal transduction pathways, which are likely induced by interactions at the plasma membrane. One such pathway that is activated in many cell types by estrogens, including E₂, is the ERK/MAPK signaling pathway. However, this signaling mechanism appears to vary greatly between cell types. For example, in cultured cortical neurons, E₂ actives ERK1/2 in a sustained manner, whereas in cerebellar neurons E₂-induced activation of ERK is transient.

Observations: In the first report, Belcher and colleagues describe the molecular mechanism by which E₂ rapidly activates ERK1/2 signaling in primary cultures of cerebellar granule cell neurons, which express ERß . E₂ rapidly activated ERK signaling via a pertussis toxin (PTX)-sensitive, G-protein-dependent mechanism that was also sensitive to PKA and Src kinase inhibitors. They also provided evidence that a PTX-insensitive pathway is activated by E₂, which results in protein phosphatase 2A activation and ERK dephosphorylation. In their second report, they demonstrate that E₂ rapidly modulates cerebellar ERK signaling in vivo and that bisphenol A (BPA), a xenoestrogen, interferes with the actions of E₂ during cerebellar development.

Significance: These results suggest there are several mechanisms through which E₂ rapidly activates intracellular signaling pathways and underscores the importance of studying the effects of E₂ in different cellular environments. In addition, the ability of E₂ to regulate ERK signaling in the cerebellum in vivo was demonstrated. Finally, the ability of a xenoestrogen to inhibit E₂ actions in vivo cautions about the potential impact xenoestrogens could have on the developing brain.

Nominated by Yoshihiro Kubo
Associate Editor, Journal of Physiology
National Institute for Physiology Sciences
ykubo{at}nips.ac.jp

Question: What accounts for the lack of cardiac abnormalities in ATP-sensitive potassium (K-ATP) channel mutants?

Background: In most tissues, K-ATP channels are 4:4 octameric complexes with four poreforming K⁺ channel subunits (Kir6.2) and four regulatory sulphonylurea receptor proteins (SUR1 in pancreatic ß-cells and neurons; SUR2A in cardiac myocytes). ATP closes the channel by binding to Kir6.2, whereas Mg²⁺ nucleotides stimulate the channel by interacting with the SUR subunits. Mutations in Kir6.2, which leads to gain of K-ATP channel function, can cause neonatal diabetes, and in some cases developmental delay, epilepsy, and muscle weakness. Paradoxically however, even though Kir6.2 is expressed in the heart, patients and mice with an abnormal Kir6.2 subunit have no obvious cardiac abnormalities.

Observations: Tammaro et al. examined the functional effects of adenine nucleotides on K-ATP channels containing mutant Kir6.2 and either SUR1 or SUR2A. Both mutations caused a similar decrease in channel sensitivity to ATP when Mg²⁺ was not present. However, when Mg²⁺ was present, the reduced sensitivity to ATP was significantly greater in SUR1-containing channels than in SUR2A-containing channels.

Significance: These experiments highlight the importance of empirically testing the sensitivity of K-ATP channels to ATP in the presence of Mg²⁺. Overall, these data suggest that the lack of effect of Kir6.2 mutations on cardiac function is a result of the greater ATP sensitivity of cardiac channels than ß-cell and neuronal channels in the presence of Mg²⁺. Thus this explains why Kir6.2 mutations cause impaired glucose homeostasis and neurological abnormalities while only minimally affecting the heart.

Nominated by Eve Marder
Editor, Journal of Neurophysiology
Brandeis University
marder{at}brandeis.edu

Question: What is the function of strychnine-sensitive glycine-gated chloride channels (GlyRs) in hippocampus?

Background: Recently, the concept that functional GlyR expression ceases early in development has been negated. It is now accepted that functional GlyRs are expressed throughout the brain. As such, neuronal inhibition may be mediated not only by GABA but also by GlyRs. Although they are known to be expressed in hippocampus and are thought to be located at extrasynaptic sites, their effects on excitability and synaptic currents are unknown.

Observations: Song et al. report that activating the GlyRs prevents synaptic action potential generation and depresses suprathreshold EPSPs to subthreshold events, thereby limiting the activity of synaptic networks in both CA1 pyramidal cells and interneurons. Moreover, blockade of GlyRs attenuates the synaptic depression, which implicates a postsynaptic mechanism of action. Finally, they demonstrate that the glycine transporter and glycine are selectively co-localized with GABAergic interneurons.

Significance: Dysfunction of inhibitory GABAergic neurons in the central nervous system leads to pathological conditions such as epilepsy and excitotoxic cell death. The co-localization of glycine and GABA described here suggests that both of these neurotransmitters provide inhibitory inputs to the hippocampus to control neuronal excitability. Thus these novel findings suggest that GlyRs could also be therapeutic targets to attenuate seizure activity and excitotoxic cell death.

Nominated by Michael Welsh
University of Iowa College of Medicine
michael-welsh{at}uiowa.edu

Question: Does the nematode Caenorhabditis elegans detect and avoid aversive bacteria via a similar mechanism as mammals?

Background: Conditioned taste aversion is a form of olfactory learning where animals avoid foods associated with noxious stimuli. C. elegans feed on bacteria in soil, including potentially pathogenic bacteria. As such, learning to avoid toxic foods is essential to the survival of C. elegans. However, the physiological changes that are associated with this learning are unknown.

Observations: Zhang and colleagues found that C. elegans acquire an aversion to pathogens within a few hours, which appears to be a form of associative learning. Further experiments demonstrated that there are aversive and attractive components of this olfactory learning mechanism. In fact, animals selectively avoided the odors from pathogenic bacteria, whereas attraction was increased for odors from nonpathogenic bacteria. Finally, they provide evidence that specific serotonin neurons increase release in response to pathogens by both transcriptional and posttranscriptional mechanisms.

Significance: These results suggest that, in C. elegans, serotonin negatively reinforces tastes and odors associated with visceral malaise. This induced avoidance of the pathogenic bacteria is analogous to a conditioned taste-aversion learning mechanism in mammals and other animals. Thus this suggests that signaling intestinal malaise via serotonin may be a primitive and conserved mechanism in all animals since serotonin receptors are the targets of anti-nausea drugs in humans.

Nominated by Michael Welsh
University of Iowa College of Medicine
michael-welsh{at}uiowa.edu

Question: What can the zebrafish elucidate about variations in human skin color?

Background: Melanin is the pigment found in organelles (melanosomes) that has a key role in determining skin color and protecting against ultraviolet radiation. Although human albinism genes have been cloned and over 100 genes are known that affect coat color in mice, the genetic determinants of human skin color have remained enigmatic. The recessive mutation in the zebrafish known as golden induces hypopigmentation of its melanin-rich stripes. However, the gene underlying this phenomenon and any potential relationship of this gene to variations in human skin color has not been determined.

Observations: Lamason et al. identified the golden gene as a putative cation exchanger SLC24A5 that appears to modulate vertebrate pigmentation via its effect on melanosome morphogenesis. The sequence of SLC24A5 was found to be highly conserved in vertebrates, and when human SLC24A5 mRNA was injected into golden zebrafish embryos it rescued melanin pigmentation, indicating functional conservation. Finally, a single nucleotide polymorphism (SNP) of the human gene was identified.

Significance: There are numerous genes that contribute to differences in skin pigmentation. However, these data suggest that SLC24A5 can account for some of the natural variations in human skin tones since when pigmentation levels were measured they found that differences in skin melanin indices could be attributed to SLC24A5 between 25% and 38% of the time. Thus this supports the idea that the SLC24A5 gene has undergone a natural selection process in Europeans, which may have evolved to allow greater sunlight absorption and thus more vitamin D production.

This Article Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via Google Scholar Google Scholar Search for Related Content