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Edited by Christopher D. Verrico
Elementary mechanisms producing facilitation of Cav2.1 (P/Q-type) channels. Chaudhuri D, Issa JB, Yue DT. J Gen Physiol. In press.
Nominated by Olaf Andersen
Editor, Journal of General Physiology
Cornell University
sparre{at}med.cornell.edu
Question: Will single-channel analysis support the theory that the COOH- and NH2-terminal lobes of calmodulin (CaM) are spatially selective for Ca2+?
Background: CaV2.1 channels form a complex with CaM, which regulates the channel by acting as a Ca2+ sensor. Macroscopic current recordings from numerous channels suggest the Ca2+ binding to the COOH-terminal lobe of CaM facilitates channel opening that appears preferentially responsive to local Ca2+ influx through the channel to which CaM is attached. In contrast, Ca2+ binding to the NH2-terminal lobe inactivates channel opening, and this process is preferentially triggered by Ca2+ entry through channels at a distance (global Ca2+ influx). The latter feature is biologically crucial: this property permits channels to integrate Ca2+ feedback among a spatially distributed collection of Ca2+ sources without being "blinded" by the intense Ca2+ influx of each individual channel.
Observations: Chaudhuri et al. used single-channel analysis of CaV2.1 channels to test directly whether this dichotomy of spatial Ca2+ selectivity actually holds true. By definition, a single channel can only produce a local but not global Ca2+ signal. Their data showed that only facilitation (but not inactivation) was present in this context, furnishing direct evidence for local/global Ca2+ preference. They also determined the mechanism underlying the Ca2+-dependent facilitation of CaV2.1 current mediated by the COOH-terminal lobe of CaM. Their recordings, which agree with findings using macroscopic current recordings, reveal that CaM-dependent facilitation is produced by its detection of local (as opposed to global) changes in Ca2+ concentration.
Significance: These results contribute substantially to our understanding of calcium channel biophysics and function, and directly support the proposed spatial Ca2+ selectivity of the terminal lobes of CaM. The existence and biological significance of this selectivity is now clear, but the mechanism of this remarkable outcome remains mysterious. Since CaM-mediated regulation of CaV2.1 is hypothesized to be an important mechanism for short-term synaptic plasticity, this work may have implications for learning and memory.
Differential effects of cyclic and constant stress on ATP release and mucociliary transport by human airway epithelia. Button B, Picher M, and Boucher RC. J Physiol (February 22, 2007); doi:10.1113/jphysiol.126086.2006.
Nominated by Kim Barrett
University of California-San Diego
kbarrett{at}ucsd.edu
Question: Does cyclic and constant stress affect ATP release and mucociliary clearance (MCC) in a similar manner?
Background: MCC represents the primary innate defense mechanism to protect the lungs against inhaled organisms and particles. Inhaled particles bind to a secreted mucus layer known as the airway surface liquid (ASL) layer, which is critical for proper lung defense. Accumulating evidence suggests that the concentration of ATP within the ASL regulates the activity of Na+ and Cl– channels via activation of P1 and P2 purinoceptors, which controls the amount of liquid in the ASL to optimize mucus clearance. Button and colleagues hypothesized that cyclic compressive stress (CCS), which mimics normal tidal breathing, regulates ASL volume through ATP release and stimulation of purinoceptor-mediated secretion.
Observations: Button and colleagues found that mechanical stresses generated during normal breathing increased the rate of ATP release by airway epithelial cells, which leads to activation of purinoceptors. The net result is a shift in the pattern of ion transport from absorption to secretion, resulting in liquid secretion and acceleration of MCC. However, nonoscillatory stress did not stimulate ATP release, ion transport, or MCC. In cystic fibrosis (CF) cultures, which are ASL depleted due to unregulated fluid absorption, CCS produced some ASL volume secretion; although less than that observed in normal cultures, it was enough to restore MCC.
Significance: These findings highlight the importance of rhythmic mechanical stress for improving airway defense, which suggests that, during asthma-associated bronchoconstriction, the stresses generated would not cause stimulation of ASL volume or MCC. However, ATP release induced by mechanical stresses may account for the preservation of MCC in CF patients, before the onset of chronic airway obstruction.
LRP6 mutation in a family with early coronary disease and metabolic risk factors.
Mani A, Radhakrishnan J, Wang H, Mani A, Mani MA, Nelson-Williams C, Carew KS, Mane S, Najmabadi H, Wu D, Lifton RP. Science 315: 1278–1282, 2007.
Nominated by Michael Caplan
Associate Editor, Physiology
Yale University School of Medicine
michael.caplan{at}yale.edu
Question: Can a common genetic link be found for the metabolic risk factors associated with the metabolic syndrome?
Background: Metabolic risk factors for coronary artery disease are known to cluster more often than expected by chance. These risk factors include hypertension, high triglycerides, high LDL, low HDL, diabetes, and obesity. However, the underlying mechanisms that account for this clustering have been unknown.
Observations: In the current study, Mani et al. identified a family with an extraordinary prevalence of early coronary artery disease that showed apparent autosomal dominant transmission. Genetic analysis demonstrated linkage to a segment of chromosome 12 that included the gene encoding LDL receptor-related protein 6 (LRP6), a co-receptor in the Wnt signaling pathway. When LRP6 was sequenced, affected family members were found to have a mutation that altered a highly conserved amino acid in the extracellular domain. This mutation was not found in unaffected family members or unrelated control subjects. Mutation carriers showed hypertension, high LDL, high triglycerides, elevated blood glucose, and low bone density, whereas HDL levels and body mass index were normal.
Significance: Although the mutation identified in this study is probably extremely rare, it identifies a pathway that regulates multiple metabolic risk factors and is therefore relevant for understanding the pathophysiology of coronary disease. Although other factors are likely involved, genetically or environmentally induced altered Wnt signaling may be responsible for the development of clusters of risk factors in some people. This intriguing possibility suggests that treatments targeting this pathway could impact multiple risk factors. Finally, it is speculated that this mutation might mimic the effect of obesity, which is believed to be a common contributor to metabolic syndrome but was absent in this family.
Targeting of diacylglycerol degradation to M1 muscarinic receptors by beta-arrestins.
Nelson CD, Perry SJ, Regier DS, Prescott SM, Topham MK, Lefkowitz RJ. Science 315: 663–666, 2007.
Nominated by Michael Caplan
Associate Editor, Physiology
Yale University School of Medicine
michael.caplan{at}yale.edu
Question: How does ß-arrestin regulate diacylglycerol (DAG) activity?
Background: G-protein-coupled receptors (GPCRs), also known as seven transmembrane receptors, are a protein family of receptors that, when activated by an extracellular signal (ligand binding), undergo conformational changes that lead to the intracellular activation of G proteins, which initiates the production of second messengers such as DAG. Inactivation of DAG is known to occur via its metabolism by members of the diacylglycerol kinases (DGKs), which create phosphatidic acid (PA). However, because ß-arrestin regulates the recruitment of phosphodiesterases to receptors that stimulate cAMP, and ß-arrestin binding to the receptor limits G-protein activation in the homologous desensitization process, Nelson et al. sought to determine whether it has a role in inactivating DAG.
Observations: ß-Arrestin was found to regulate the recruitment of DGKs to receptors that stimulate production of diacylglycerol (e.g., muscarinic receptors). Under basal conditions, all seven DGKs examined could directly associate with ß-arrestin when the molecules are overexpressed. Nelson et al. also used mutants to determine that ß-arrestin binds to a cysteine-rich domain present in all DGKs, which accounts for its interaction with all the enzyme isoforms.
Significance: These findings were not necessarily predictable because there is no structural, functional, or sequence homology between the phosphodiesterases and the DGKs. Nonetheless, ß-arrestin appears to have a dual role in regulating DAG signaling; it slows the rate of second messenger generation and enhances the rate of DAG degradation. This suggests that there is a more general role for ß-arrestin in inducing receptor desensitization and signal termination. Given the widespread distribution of DAG as a second messenger for many receptors, this role of ß-arrestin may have far-reaching physiological consequences.
Gene profiling during regression of pressure overload-induced cardiac hypertrophy. Yang DG, Choi BY, Lee YH, Kim YG, Cho MC, Hong SE, Kim DH, Hajjar RJ, Park WJ. Physiol Genomics (February 27, 2007); doi:10.1152/physiologenomics. 00246.2006.
Nominated by Allen Cowley
Medical College of Wisconsin
cowley{at}mcw.edu
Question: Can a gene be identified as a key regulator of cardiac hypertrophy regression?
Background: Cardiac hypertrophy is a compensatory mechanism that involves thickening of the heart muscle (myocardium) and occurs in response to a variety of extrinsic and intrinsic stimuli that impose stress, such as high blood pressure. Although this is initially helpful, excessive hypertrophy can occur and cause cell death, which increases the stress and causes the surviving cells to grow even larger. Although the underlying cause of the hypertrophy (e.g., high blood pressure) can be treated, the hypertrophy may or may not regress completely, which suggests that it may be beneficial to directly treat the hypertrophy.
Observations: Yang et al. sought to elucidate the molecular mechanism underlying the regression of cardiac hypertrophy. Using DNA microarray analysis, they identified a set of genes specifically induced during the regression period. Of the 52 genes that were specifically upregulated during the regression period one gene, Eyes absent 2 (Eya2), was overexpressed in rat neonatal cardiomyocytes. This resulted in complete protection from the development of cardiomyocyte hypertrophy.
Significance: This research suggests that Eya2 may be a key regulator of cardiac hypertrophy. Although it is still necessary to determine whether Eya2 is an inhibitor or regressor of cardiac hypertrophy, it may represent a novel target for modifying regression therapeutically.
Characteristics of skeletal muscle mitochondrial biogenesis induced by moderate-intensity exercise and weight loss in obesity. Menshikova EV, Ritov VB, Ferrell RE, Azuma K, Goodpaster BH, Kelley DE. J Appl Physiol (March 1, 2007); doi:10.1152/japplphysiol.01228.2006
Nominated by Jerry Dempsey
Editor, Journal of Appied Physiology
University of Wisconsin
jdempsey{at}wisc.edu
Question: Does moderate-intensity exercise and weight loss in obese individuals induce an increase in mitochondrial cristae?
Background: The oxidative capacity of skeletal muscle is dependent on the physical demands the muscle is subjected to over time. Thus high-intensity activities in fit persons increases mitochondrial biogenesis and the oxidative capacity of skeletal muscle, which is characterized by an increase in mitochondrial DNA (mtDNA). Similarly, when obese people are subjected to moderate-intensity exercise, they experience a similar increase in oxidative capacity. However, in contrast to the adaptive response to vigorous exercise, namely an increase in mtDNA, the adaptive response to the moderate-intensity exercise does not share this characteristic. Thus Menshikova et al. hypothesized that a different pattern of mitochondrial adaptation must occur in the latter situation.
Observations: Basing their theory on the knowledge that mitochondrial biogenesis occurs in yeast via an increase in the inner mitochondrial membrane (cristae) density, Menshikova et al. measured the amount of cristae in obese subjects on a moderate-intensity exercise program. As previously reported, they found no change in the mtDNA content of skeletal muscle. However, as predicted, they found that the exercise induced an increase in the mitochondrial cristae.
Significance: These findings suggest that a different pattern of mitochondrial biogenesis occurs in obese adults who are subjected to moderate-intensity exercise versus the adaptation that occurs in response to high-intensity activity. Although many questions remain unanswered, it will be interesting to see whether obese persons have an impaired capacity for mtDNA proliferation. These findings may be of particular relevance to the study of obesity.
Protein kinase C regulates vascular myogenic tone through activation of TRPM4. Earley S, Straub SV, Brayden J. Am J Physiol Heart Circ Physiol (February 9, 2007); doi:10.1152/ajpheart.01286.2006.
Nominated by Alberto Nasjletti
Editor, American Journal of Physiology—Heart and Circulatory Physiology
New York Medical College
alberto_nasjletti{at}nymc.edu
Question: Is the transient receptor potential (TRP) channel, TRPM4, involved in myogenic tone?
Background: The ability of arteries to constrict or dilate in response to fluctuations in blood pressure requires the presence of a basal vascular myogenic tone. PKC activity is essential for myogenic tone, as inhibition of PKC leads to loss of tone. Myogenic constriction is mediated by pressure-induced smooth muscle cell depolarization and Ca2+ influx via voltage-dependent Ca2+ channels (VDCCs). Recently, TRPM4 was determined to be necessary for pressure-induced depolarization, VDCC activation, and vasoconstriction of arteries. Thus it was postulated that PKC-induced activation of TRPM4 may be involved in myogenic tone.
Observations: Earley and associates found that PKC inhibition attenuated myogenic vasoconstriction, whereas stimulating PKC activity enhanced vasoconstriction. In fact, PKC activation increased the Ca2+ sensitivity of TRPM4-dependent currents, induced smooth muscle cell depolarization and vasoconstriction. These effects were reduced when TRPM4 expression was suppressed.
Significance: These results suggest that PKC stimulates TRPM4-dependent currents by increasing sensitivity to Ca2+, which is a critical mechanism for mediating the myogenic tone of cerebral arteries. As such, PKC activity may contribute to disrupted arterial function in some pathophysiological conditions. Therefore, TRPM4 may represent a novel target for pharmaceutical interventions.
Balanced inhibition and excitation drive spike activity in spinal half-centers.
Berg RW, Alaburda A, Hounsgaard J. Science 315: 390–393, 2007.
Nominated by Michael Welsh
University of Iowa
michael-welsh{at}uiowa.edu
Question: Does the synaptic excitation and inhibition associated with limb movements occur in phase?
Background: In the cerebral cortex, there are inhibitory and excitatory outputs that are continuously active, a process that allows the system to be highly responsive. In contrast, the current theory of how motor circuits in the spinal cord generate rhythmic movements suggests that the inhibitory and excitatory outputs alternate their activity to produce movement. This theory was directly tested by Berg et al.
Observations: Berg et al. determined that the intensity of excitation and inhibition in spinal motoneurons varies, not out of phase as expected, but in phase during rhythmic network activity that underlies movement. They also show that, when the inhibition to the motor neurons is blocked, the intervals between spikes become more regular.
Significance: These findings suggest that the spinal cord generates movement by using mechanisms that are similar to those used in the brain. One advantage of this system is that, even when the excitatory input is constant, a large range of outputs can still be produced (i.e., neuronal circuits controlled by both excitation and inhibition have a broader dynamic range). Perhaps more important is the model system used in these experiments. The turtle scratch reflex system is more concise and more easily controlled than brain activity. Thus the turtle scratch reflex system should provide a good model system for determining what advantages are gained by having both inhibitory and excitatory outputs.
Regulation of Drosophila life span by olfaction and food-derived odors.
Libert S, Zwiener J, Chu X, Vanvoorhies W, Roman G, Pletcher SD. Science 315: 1133–1137, 2007.
Nominated by Michael Welsh
University of Iowa
michael-welsh{at}uiowa.edu
Question: Can odors affect the lifespan of a fruit fly?
Background: Dietary restriction is known to increase the lifespan of many species, in some cases extending an animal’s life by up to 50%. However, the underlying mechanism responsible for this phenomenon is unknown. Previous research has shown that destroying olfactory neurons in the worm C. elegans prolongs life. Moreover, Pletcher and colleagues recently determined that food availability and age strongly affect genes encoding proteins that bind to odorants, suggesting a link between olfaction and lifespan.
Observations: To investigate whether odors could affect fly longevity, dietary restricted fruit flies (Drosophila), which live longer than normal flies, were exposed to the scent of yeast. Remarkably, the flies’ lifespans were shortened by 6 to 18% even though the odorants did not affect feeding behavior. Next, they found that knocking out the broadly expressed odorant receptor Or83b increased lifespan by up to 56%, which could be reversed by expressing the Or83b transgene in mutant flies. Interestingly, lifespan was further increased in Or83b knockout flies after dietary restriction.
Significance: Collectively, these results suggest that odors can affect lifespan, and even though some component of the dietary restriction response is olfactory-dependent, the odorant response occurs principally through a diet-independent pathway. These findings suggest that dietary restriction increases lifespan not only because of the decreased availability of food but also because of the decreased perception of food. This work highlights the pivotal role environmental perceptions can play in the lifespan of an animal.
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