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Edited by Christopher D. Verrico
Gating and inward rectifying properties of the MthK K+ channel with and without the gating ring.
Li Y, Berke I, Chen L, Jiang Y. J Gen Physiol 129: 109–120, 2007; 10.1085/jgp.200609655.
Nominated by Olaf Andersen
Editor, Journal of General Physiology
Cornell University
sparre{at}med.cornell.edu
Question: What is the molecular/structural basis for the gating properties of the Ca2+-gated K+ channel MthK?
Background: MthK is a Ca2+-gated K+ channel that contains conserved COOH-terminal ligand-binding domains named RCK (for regulating the conductance of K+ channels). A functional MthK channel requires eight RCK Ca2+ binding domains to form an octameric gating ring on the intracellular side of the pore. Hence, when eight Ca2+ ions are bound, one per RCK domain, a conformational change occurs that results in an opening of the pore.
Observations: Using single-channel recordings, Li and colleagues analyzed the ion conductance and gating properties of MthK channels as a function of [Ca2+] and [H+]. They found that MthK can be activated by Ca2+ in a pH-dependent manner. If the pH was below 7.5, the channel was insensitive to Ca2+, as the pH increased above 7.5, the channels’ Ca2+ sensitivity increased, whereas the cooperativity of the Ca2+ activation decreased. In addition, higher pH alone could also activate the channel. An intracellular divalent cation was found to block the pore of the MthK channel in a voltage-dependent manner, which implies the channel has the property of inward rectification. Finally, two gating processes could be attributed to the channels: a slow process that was affected by Ca2+ and pH, and a fast process that is independent of Ca2+ and H+.
Significance: Although there are several studies of the crystal structures of the MthK channel in different states, they only provide a partial understanding of the dynamics of the channel opening and closing. Based on the present electrophysiological and previous structural studies, a minimal molecular model is proposed to account for the gating processes in MthK, which includes four states and three conformational equilibria.
Transgenic mice with a reduced core body temperature have an increased life span.
Conti B, Sanchez-Alavez M, Winsky-Sommerer R, Morale MC, Lucero J, Brownell S, Fabre V, Huitron-Resendiz S, Henriksen S, Zorrilla EP, de Lecea L, Bartfai T. Science 314: 825–828, 2006.
Nominated by Michael Caplan
Associate Editor, Physiology
Yale University School of Medicine
michael.caplan{at}yale.edu
Question: Is the reduction in core body temperature induced by calorie restriction requisite for increasing longevity?
Background: Mammalian temperature homeostasis is regulated by the preoptic area (POA) of the hypothalamus. Thus local or peripheral changes in temperature are sensed by the POA, which cooridantes a thermoregulatory response to maintain core body temperature (CBT). Lowering CBT slows the aging process and extends the lifespan of cold-blooded animals. Lifespan extension in warm-blooded animals is achieved by reducing caloric intake, a dietary regimen that also reduces CBT. However, it is not clear whether the calorie restriction alone can increase lifespan or whether the reduction in CBT was a necessary phenomenon.
Observations: Based on the knowledge that insertion of heat probes into the POA causes a reduction in body temperature, Conti et al. hypothesized correctly that inducing the production of large quantities of uncoupling protein 2 near the preoptic area would produce heat, which would diffuse to other brain structures, including the preoptic area. In turn, the extra heat induced a continuous reduction of the CBT of the mice, lowering it 0.3–0.5°C. This lowered CBT resulted in significantly longer median lifespans. Interestingly, this effect was more pronounced in females, whose median lifespan was extended about 20% vs. 12% in males. Although the transgenic mice showed no change in caloric intake or physical activity, they did gain weight.
Significance: This is the first time that changes in body temperature have been shown to affect lifespan in warm-blooded animals independent of changes in diet. These findings are particularly intriguing given the abundance of evidence that demonstrates increased weight correlates with a shortened lifespan.
Ion selectivity in a semisynthetic K+ channel locked in the conductive conformation.
Valiyaveetil FI, Leonetti M, Muir TW, Mackinnon R. Science 314: 1004–1007, 2006.
Nominated by Michael Caplan
Associate Editor, Physiology
Yale University School of Medicine
michael.caplan{at}yale.edu
Question: What confers the selectivity of potassium channels to K+ over other ions?
Background: Ion channels are proteins that form pores to allow the flow of ions down their electrochemical gradient. K+ channels are selectively permeable to K+ over other ions, such as Na+. The selectivity filter of the ion channel is what distinguishes K+ ions from Na+ ions. This selectivity is accomplished by K+-induced conformational changes that occur within the channel. When K+ ions are present in the channel, it conforms to the "conductive" conformation. In contrast, when K+ concentrations are low and Na+ ions are present, the channel collapses and adapts to the "nonconductive" structure to exclude Na+.
Observations: Valiyaveetil et al. sought to determine whether the K+-induced conformational change to the channel is important for selectivity. A mutant K+ channel was synthesized that did not allow a conformational change to take place, thus elminating the nonconductive conformation. Similar to the wild-type channel, the mutant channel prevented Na+ conduction in the presence of K+. However, unlike the wild-type channel, the mutant channel conducted Na+ in the absence of K+.
Significance: These results suggest that K+ channels, under normal low K+ conditions, prevent Na+ conduction because Na+ favors the nonconductive conformation, not because Na+ cannot diffuse across the conductive filter. In addition, another fundamental aspect of the channel borne out by these studies is that K+ prevents Na+ conduction because the multiple binding sites in the conductive filter preferentially bind K+ over Na+. Given the near ubiquitous expression of K+ channels, these results may have widespread implications for understanding several disease states.
The effects of acute oral antioxidants on diving-induced alterations in cardiovascular function.
Obad A, Palada I, Valic Z, Ivancev V, Bakovic D, Wisloff U, Brubakk AO, Dujic Z. J Physiol 578: 859–870, 2007; 10.1113/jphysiol.2006.122218.
Nominated by Michael Joyner
Associate Editor, Journal of Physiology
Mayo College of Medicine
joyner.michael{at}mayo.edu
Question: Can acute exposure to antioxidants prevent the cardiovascular effects of diving?
Background: Although recreational diving has become a popular pastime for millions of people, it is associated with environmental stresses that affect hemodynamics and cardiovascular function. For example, field scuba diving causes an increase in pulmonary artery pressure and endothelial dysfunction. Obad et al. previously demonstrated that chronic (4 weeks) exposure to the antioxidants vitamin C and E reversed the acute endothelial dysfunction observed after diving. Here, they sought to determine whether acute exposure to antioxidants would attenuate the negative effects of diving on cardiovascular and endothelial function.
Observations: Obad and colleagues demonstrated that scuba diving, at depths and durations similar to those enjoyed by recreational divers, can cause modest reductions in cardiovascular and blood vessel function for several days after the dive. However, pre-dive ingestion of vitamins C (2 g) and E (400 IU) partially prevented some of the negative effects of the dive, suggesting that diving-associated oxidative stress contributed to the changes.
Significance: Although the changes in cardiovascular and blood vessel function were not a threat to the health of the divers, this study raises the possibility that routine pre-dive supplementation with antioxidant vitamins would be beneficial. This study is likely to be of interest to recreational divers and also to those involved in military and industrial diving.
Cardiac neural crest ablation inhibits compaction and electrical function of conduction system bundles.
Gurjarpadhye A, Hewett KW, Justus C, Wen X, Stadt H, Kirby ML, Sedmera D, Gourdie RG. Am J Physiol Heart Circ Physiol (December 15, 2006); 10.1152/ajpheart.01017.2006.
Nominated by Alberto Nasjletti
Editor, American Journal of Physiology Heart and Circulatory Physiology
New York Medical College
alberto_nasjletti{at}nymc.edu
Question: What role, if any, do cardiac neural crest cells play in the development of the bundle of His?
Background: The cardiac conduction system involves the generation of an electrical impulse from the sinoatrial node (SA node) that is conducted by the atrioventricular node (AV node) to the bundle of His, which transmits the impulses to the Purkinje fibers that innervate the ventricles and cause the heart to contract. One essential feature of the His-Purkinje conduction system is that it is electrically isolated from surrounding tissues to prevent dissipation of the excitatory impulse. Although an association has been made between the development of the cardiac conduction system and neural crest cells, whether neural crest cells affect the differentiation and/or function of the bundle of His was not known.
Observations: Gurjarpadhye et al. sought to determine whether ablation of the cardiac neural crest cells would affect the cardiac conduction system. They provide evidence consistent with a role of neural crest cells in the development of the His bundle. In fact, they found that neural crest ablation resulted in His bundle cells maintaining electrical connections with surrounding myocardium. They also note the requirement for neural crest cells in the development of insulation in cardiac conduction bundles and nerves. Moreover, His bundles from ablated embryos did not undergo the normal remodeling associated with development. Finally, whereas the His bundle diameter thinned in control hearts, ablation resulted in His bundle diameters that did not undergo such thinning.
Significance: These data suggest that the cardiac neural crest plays a role in the differentiation, specialization, and electrical isolation of the His-Purkinje conduction system. Perhaps these findings will aid in elucidating the pathology of some cardiac diseases, such as infrahisian heart block, which is a dysfunction in the electrical conduction system of the bundle of His.
Lowest neonatal serum sodium predicts sodium intake in low-birthweight children.
Shirazki A, Weintraub Z, Reich D, Gershon E, Leshem M. Am J Physiol Regul Integr Comp Physiol (December 14, 2006); 10.1152/ajpregu.00453.2006.
Nominated by Pontus Persson
Editor, American Journal of Physiology—Regulatory, Integrative and Comparative Physiology
Humboldt University
pontus.persson{at}charite.de
Question: Is neonatal diuretic treatment predictive of sodium intake in children?
Background: The amount of sodium individuals consume varies widely. The reasons for the wide variations in sodium consumption are unknown, but because long-term sodium intake is a key marker for obesity, it is an important question. Previous work by this group found that children who received neonatal diuretic therapy excreted more sodium than controls, which suggests they consumed more sodium. Thus, in the current study, they hypothesized that dietary sodium consumption in children would be predicted by neonatal diuretic treatment.
Observations: Shirazki et al. examined the sodium appetite of children (ages 8–15 yr) born prematurely and whether they received neonatal diuretic treatment during their first postnatal month. They also assessed serum sodium measurements of the infant’s as an index of sodium loss. In contrast to their hypothesis, dietary sodium intake in children was predicted by neonatal lowest serum sodium, not neonatal diuretic treatment. This was true of two ethnic groups and both boys and girls. Finally, they found that the most severe cases of low-sodium blood serum was found in children who consumed significantly more sodium per day and weighed 30% more than their peers.
Significance: This study suggests that long-term intake of sodium is impacted by neonatal events. In infants, low-sodium blood serum, not neonatal diuretic treatment, gestational age, or birthweight, was predictive of an increase in sodium consumption in childhood. The relationship between neonatal serum sodium, future sodium intake, and obesity should be cause for concern and made clear to parents with children who have low neonatal serum sodium.
Lack of central nitric oxide triggers erectile dysfunction in diabetes.
Zheng H, Bidasee KR, Mayhan WG, Patel KP. Am J Physiol Regul Integr Comp Physiol. (November 9, 2006); 10.1152/ajpregu.00429.2006.
Nominated by Pontus Persson
Editor, American Journal of Physiology—Regulatory, Integrative and Comparative Physiology
Humboldt University
pontus.persson{at}charite.de
Question: Is the erectile dysfunction (ED) associated with diabetes mediated by a central mechanism?
Background: ED is a common complication of diabetes; however, the pathophysiological mechanisms that underlie this dysfunction are unknown. Sildenafil (Viagra) works peripherally and is effective 50% of the time in diabetic patients, which implies another mechanism may underlie the dysfunction in some patients. Centrally, nitric oxide (NO) within the paraventricular nucleus (PVN) is putatively synthesized in response to N-methyl-D-aspartic acid (NMDA) receptor activation to mediate penile erection. Thus the possibility that NMDA/NO-induced penile erection was impaired in the PVN was explored in diabetic rats.
Observations: The authors compared induced erection via the PVN in control and diabetic male rats. The results of the study showed that NMDA-induced erections were blunted in the diabetic rats and that sodium nitroprusside (an NO donor)-induced responses were also significantly blunted. In addition, the expression of the neuronal NO synthase (nNOS) isoform was dramatically reduced in the PVN region from diabetic rats but not in two other adjacent forebrain regions. Finally, the erectile response was recovered by over expression of nNOS by gene transfer using an adenoviral transfection into the PVN.
Significance: This study addresses a very important and under-investigated area of research: the role of the central nervous system in erection. These results support the hypothesis that a central NO mechanism within the PVN may contribute to the ED observed in diabetes. Examining the mechanism of diabetes-induced ED is very topical given the alarming rate at which diabetes is increasing.
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