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Edited by Christopher D. Verrico
The mechanism of fast-gate opening in ClC-0. Engh AM, Faraldo-Gomez JD, and Maduke M. J Gen Physiol doi:10.1085/jgp.200709759.2007.
The role of a conserved lysine in chloride- and voltage-dependent ClC-0 fast gating. Engh AM, Faraldo-Gomez JD, and Maduke M. J Gen Physiol doi:10.1085/jgp.200709760.2007.
Nominated by Olaf Andersen
Editor, Journal of General Physiology
Cornell University
sparre{at}med.cornell.edu
Question: What structural changes underlie fast gating in ClC-0 chloride channels?
Background: The CLC family of chloride channels and transporters is expressed ubiquitously and functions both in plasma membranes and in intracellular organelles. The prototypical member of the family, ClC-0, is a dimer, and both subunits function as pores. The slow gating mechanism of ClC-0 closes both pores simultaneously, whereas the fast gating mechanism governs the independent voltage- and chloride-dependent opening and closing of each pore. Previous analysis of single-channel data led to a five-state model that explains the effects of voltage and chloride on the opening rate constant for each pore. Engh et al. re-investigated this model to set the stage for exploring the effects of mutations on gating and understanding the structural changes that occur during each gating step.
Observations: Engh et al. used macroscopic patch recordings that reproduced the effects of voltage and chloride that were previously reported on the fast gating, and they fit this data to the five-state model. However, on further analysis of their data, they found several contrasting features that led them to conclude that a simpler four-state model could account for the fast gating of ClC-0 and that the chloride-binding step itself is voltage dependent, not voltage independent as previously supposed. In the second paper, mutations at the highly conserved K149 position were shown to exert a significant effect on the voltage-dependent channel-opening step, and the degree of this effect was highly sensitive to side-chain size and shape. Computational analysis of a mutant structural homology model suggests that a K149 mutation affects chloride binding to all three chloride binding sites in the pore.
Significance: These results help us to better understand the mechanism of fast-gate opening in ClC-0 channels and suggest some of the structural changes that are likely to underlie this gating. This study highlights that chloride movement could be involved in all the kinetic steps in fast-gate opening and supports the notion that ClC-0, despite being a channel, has a tightly packed chloride-coordinating structure similar to the prokaryotic antiporters, such that even small perturbations in structure near the pore greatly affect chloride movement and hence gating. Defects in these proteins are responsible for several human disorders including epilepsy and kidney and bone disease; thus these findings may be important for understanding the etiology of these, and other, pathological conditions.
Beneficial effects of glucagon-like peptide-1 (GLP-1) on endothelial function in humans: dampening by glyburide but not by glimepiride. Basu A, Charkoudian N, Schrage W, Rizza RA, Basu R, and Joyner MJ. Am J Physiol Endocrinol Metab (August 21, 2007); doi:10.1152/ajpendo.00373.2007.
Nominated by Patricia Brubaker
Associate Editor, American Journal of Physiology—Endocrinology and Metabolism
University of Toronto
p.brubaker{at}utoronto.ca
Question: Does glucagon-like peptide-1 (GLP-1) directly affect endothelial function in humans?
Background: Drugs that increase GLP-1 activity have been shown to improve glycemic control in clinical trials, and administration of a GLP-1 receptor agonist in combination with sulphonylureas (SU) has recently been approved for the treatment of Type 2 diabetes. GLP-1 has also been implicated in cardiac and endothelial functions. However, whether the effects of GLP-1 on cardiac and endothelial functions result from changes in insulin, C-peptide and/or glucagon, or result from direct effects on injured myocardium or endothelium is unknown.
Observations: Basu et al. sought to determine whether the effects of GLP-1 on cardiac and endothelial function are independent of hormonal changes. They found that GLP-1 per se increases baseline and acetylcholine-induced vasodilatation independently of alterations in glucose or insulin, an effect that was differentially modulated by various anti-diabetic agents (e.g., sulfonylureas). Their data imply that GLP-1 enhances endothelium-dependent vasodilatation, which suggests an upregulation of endothelial nitric oxide synthase system.
Significance: These data demonstrate that in healthy humans GLP-1 per se has direct beneficial effects on endothelium-dependent vasodilatation that is differentially modulated by sulphonylureas. In fact, the endothelial benefits of GLP-1-based therapy may be largely mitigated by concomitant utilization of the sulphonylurea glyburide. Additional research is needed to determine the effects of GLP-1 on the endothelium in people with Type 2 diabetes, with and without sulphonylureas.
Genetic and environmental influences on skeletal muscle phenotypes as a function of age and sex in large, multi-generational families of African Heritage. Prior SJ, Roth SM, Wang X, Kammerer C, Miljkovic-Gacic I, Bunker CH, Wheeler VW, Patrick AL, and Zmuda JM. J Appl Physiol (July 26, 2007). doi:10.1152/japplphysiol.00120.2007.
Nominated by Jerry Dempsey
Editor, Journal of Applied Physiology
University of Wisconsin
jdempsey{at}wisc.edu
Question: What contribution do genetic and environmental factors have on skeletal muscle phenotypes?
Background: Sarcopenia, a decline in muscle mass, and a decline in muscle strength occur in humans after they reach 40 yr old. This phenomenon is associated with reduced bone density, aerobic capacity, and resting metabolic rate, which may predispose people to falls, insulin resistance, Type 2 diabetes, dyslipidemia, and hypertension. Although the influence of physical activity on skeletal muscle traits has been explored in numerous studies, the influence of genetics has only recently come under scrutiny. However, the heritability of skeletal muscle phenotypes in non-white populations is relatively unexplored, as are the effects of sex and age.
Observations: Prior et al. hypothesized that heritability and environmental contributions to skeletal muscle phenotypes would diverge as a function of age and sex in families of African descent. They determined that there was a significant contribution of heritability to lean soft tissue mass and muscle cross-sectional area. They also found that the estimates of heritability were different between men and women and between younger and older subjects. Finally, other environmental factors, such as oral contraceptive use, smoking, and history of pregnancy, were found to impact skeletal muscle phenotypes.
Significance: This is the first report of age-and sex-related differences in the heritability of lean mass, although aging is speculated to contribute additional environmental factors that reduce the relative genetic contribution to muscle phenotypes. Improved understanding of how genetic and environmental factors impact muscle phenotypes may lead to new ways to improve phenotypes and sarcopenia-related comorbidities such as obesity and metabolic abnormalities.
Inactivity, exercise training and detraining, and plasma lipoproteins. STRRIDE: a randomized, controlled study of exercise intensity and amount.
Slentz CA, Houmard JA, Johnson JL, Bateman LA, Tanner CJ, McCartney JS, Duscha BD, and Kraus WE. J Appl Physiol 103: 432–442, 2007.
Nominated by Jerry Dempsey
Editor, Journal of Applied Physiology
University of Wisconsin
jdempsey{at}wisc.edu
Question: Does exercise intensity, or amount of training, differentially affect the duration of the benefit on plasma lipoproteins during detraining?
Background: Regular physical activity has a number of beneficial effects, including a reduced risk of developing cardiovascular disease. This phenomenon is likely due, in part, to the changes that occur in lipid metabolism. In fact, the equivalent of jogging 17 miles/wk results in several beneficial effects on lipoproteins and lipoprotein particle size and number. Although the beneficial effects of exercise are well described, little is known regarding the sustainability of these effects or whether the duration of the benefits is affected by the intensity or amount of training.
Observations: Slentz et al. recruited sedentary, overweight subjects as controls or to participate in one of three exercise programs: high-amount/vigorous-intensity exercise; low-amount vigorous intensity exercise; or low-amount/moderate-intensity exercise. Moderate-intensity exercise, but not vigorous-intensity exercise, resulted in a sustained reduction in very low-density lipoprotein-triglycerides that persisted for 15 days after the exercise program had stopped. The high-amount group was determined to have improved high-density lipoprotein (HDL)-cholesterol (HDL-C), HDL particle size, and large HDL levels, which also persisted for 15 days postexercise.
Significance: These data suggest that the effects of exercise training on lipoproteins are sustained for at least 2 wk after the last exercise session. Perhaps more intriguing is the differential benefits observed under different exercise intensities. This suggests that patients may benefit more if an exercise program is tailored to their particular lipoprotein abnormality. Thus patients with hypertriglyceridemia would be put on a moderate-intensity exercise program, whereas those patients whose goal is to improve HDL-C, HDL particle size, and large HDL are prescribed a high-amount training program.
Depolarization activates the phospho-inositide phosphatase Ci-VSP, as detected in Xenopus oocytes coexpressing sensors of PIP2.
Murata Y, and Okamura Y. J Physiol 583: 875–889, 2007.
Nominated by Toshi Hoshi
Associate Editor, Journal of Physiology
University of Pennsylvania
hoshi{at}hoshi.org
Question: Does hyperpolarization or depolarization induce Ciona voltage-sensor containing phosphatase (Ci-VSP) activity?
Background: Voltage-gated ion channels are perhaps best known for their function in neurons where they are activated by changes in electrical potential difference to propagate electrical signals. Most voltage-gated ion channels share a voltage sensor domain (VSD) and a pore domain. Recently, a VSD-containing protein, Ci-VSP, was identified that translates electrical inputs into chemical signals but lacks a pore domain. However, it is not clear whether depolarization or hyperpolarization induces Ci-VSP phosphatase activity. Moreover, there is no adequate explanation why there is a large gap in the voltage dependency between the charge movement of the VSD and phosphatase activities.
Observations: Murata and Okamura set out to determine the relationship between the charge carried by the VSD and phosphatase activity by measuring potassium channel activities. In contrast to the original hypothesis, they found that phosphatase is activated by depolarization, not hyperpolarization. The gap of voltage dependency between the charge movement and phosphatase activity was determined to be due to the limited dynamic range of sensitivity of GIRK2 channels to phosphoinostitides. Thus the enzyme activity in Ci-VSP is changed gradually over a range of membrane potentials where the magnitude of "gating" charges of the VSD varies.
Significance: These results suggest that Ci-VSP is similar to voltage-gated Na+, Ca2+, and K+ channels in that depolarization activates effector operation and that conformational change of the VSD is translated into a downstream effector. Future research aimed at understanding the mechanism of phosphatase-voltage coupling and Ci-VSP stoichiometry may provide details on the structure-function relationships relevant to all voltage-gated channels.
Recovery of learning and memory is associated with chromatin remodelling. Fischer A, Sananbenesi F, Wang X, Dobbin M, and Tsai LH. Nature 447: 178–182, 2007.
Nominated by Julie Kauer
Brown University
julie_kauer{at}brown.edu
Question: Can memory loss be recovered by environmental enrichment or manipulation of gene expression?
Background: Long-term memory formation involves the organization of new synaptic connections, which requires gene transcription. Histone proteins form a complex with DNA, known as chromatin, and when acetylated they make DNA available for transcription. Inhibitors of histone deacetylases (HDACs) then have the potential to boost memory formation, and this has in fact been demonstrated in a mouse model. Tsai and colleagues developed a mouse model of Alzheimer’s disease, in which mice display deficits in recalling long-term memories. In this report, they explored whether environmental enrichment or HDAC inhibitors could restore access to long-term memories.
Observations: It was found that mice with induced Alzheimer’s were severely impaired on memory tasks, but when they were exposed to an enriched environment their memories improved. They found that histone acetylation and proteins involved in synapse formation were markedly increased in the hippocampi of mice that had been exposed to the enriched environment. Next, they determined that administration of a HDAC inhibitor also led to a significant improvement in the performance of memory tasks. In fact, the inhibitor induced an increase in the levels of synaptic proteins in the hippocampus and anterior cingulate cortex, just as the enriched environment had done.
Significance: It is fascinating that an enriched environment can have the same beneficial effect on memory and induce the same physiological consequences as a HDAC inhibitor. These results imply that 1) drugs aimed at inhibiting HDAC could be developed to treat Alzheimer’s and other neurodegenerative diseases in which memory is impaired and 2) mental stimulation may be just as effective as drug administration to reverse memory loss.
Remote control of neuronal activity with a light-gated glutamate receptor. Szobota S, Gorostiza P, Del Bene F, Wyart C, Fortin DL, Kolstad KD, Tulyathan O, Volgraf M, Numano R, Aaron HL, Scott EK, Kramer RH, Flannery J, Baier H, Trauner D, Isacoff EY. Neuron 54: 535–545, 2007.[CrossRef][ISI][Medline]
Nominated by Julie Kauer
Brown University
julie_kauer{at}brown.edu
Question: Can a protein be developed that allows remote spatial and temporal regulation in vivo?
Background: Empirical analyses investigating the link between neuronal activity and brain function either determine the consequences of blocking or disrupting neural activity or associate the neuronal activity with specific functions. Although these approaches are informative, the ability to manipulate the activity of specific neurons spatially and temporally would allow scientists to determine how specific neuronal cell types contribute to brain functions and behavior. In this report, the authors designed a glutamate analog on a linker that would change conformation in response to different wavelengths of light.
Observations: An artificial, light-gated ionotropic glutamate receptor (LiGluR) was genetically engineered by Szobota et al. and expressed in cultures of hippocampal neurons. When the neurons were exposed to the correct wavelength of light, the neurons were depolarized, and action potentials were generated. Subsequently, exposure to a second beam of blue light deactivated the neurons. Moreover, when expressed in zebrafish, they were unable to execute their normal escape response to a physical touch when illuminated by UV light, which was restored when the fish were illuminated with blue light.
Significance: The ability to selectively stimulate neurons is an exciting proposition since it will allow scientists to determine how specific neuronal cell types contribute to brain functions and behavior. The use of an optical switch to turn proteins off and on is ideal since it allows temporal and spatial control of the proteins’ activity and can be applied to diverse experimental conditions. Finally, the LiGluR also has the unique property that, once activated by a brief pulse of light, the channel remains open until deactivated, which makes it possible to evoke long depolarization and trains of action potentials.
Loss of mXin
, an intercalated disc protein, results in cardiac hypertrophy and cardiomyopathy with conduction defects.
Gustafson-Wagner EA, Sinn HW, Chen YL, Wang DZ, Reiter RS, Lin JL, Yang B, Williamson RA, Chen J, Lin CI, Lin JJ. Am J Physiol Heart Circ Physiol (August 31, 2007). doi:10.1152/ajpheart.00806. 2007.
Nominated by Alberto Nasjletti
alberto_nasjletti{at}nymc.edu
Question: What is role of mXin in the heart?
Background: The intercalated disc is a specialized membrane structure between adjacent cardiomyocytes, composed of three types of membrane junctions (fascia adherens, desmosomes, and gap junctions) that support synchronized contraction of cardiac tissue. The striated muscle-specific Xin protein is known to be involved in cardiac morphogenesis and two mouse Xin (mXin) genes encode mXin and mXinβ proteins, co-localized with the adherens junction component to the intercalated disc. The mXin directly interact with β-catenin.
Observations: In this report, Gustafson-Wagner et al. created mXin knockout mice that were viable because of compensation by an upregulated mXinβ. However, the mXin-null mice exhibited cardiac hypertrophy and cardiomyopathy with conduction defects due to a progressive disruption of intercalated disc structure. They determined that the mXin-null mouse hearts displayed myofilament disarray, altered connexin 43 expression and localization, and prolonged P wave and QT interval. Moreover, the expression of N-cadherin, β-catenin, and other but not all junction components were decreased in the mXin-null mice.
Significance: These results show that mouse Xin may play a vital role in cardiac function. As such, the mXin knockout mouse is a novel model of cardiac hypertrophy and cardiomyopathy with conduction defects.
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