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Edited by Christopher D. Verrico
Cardiac mass and cardiomyocyte size are governed by different genetic loci on either autosomes or chromosome Y in recombinant inbred mice.
Llamas B, Bélanger S, Picard S, Deschepper CF. Physiol Genomics 31: 176–182, 2007.
Nominated by Norbert Hübner
Associate Editor, Physiological Genomics
Max-Delbruck-Center for Molecular Medicine
nhuebner{at}mdc-berlin.de
Question: Are cardiac mass and cardiomyocyte size governed by the same genetic locus?
Background: Although left ventricular (LV) hypertrophy (LVH), which refers to a thickening of the heart muscle’s left ventricle, is not a disease, it is a marker of an underlying health problem. At the cellular level, it is unknown what LVH corresponds to, since changes in LVH occur because of differences in the number or size of cardiomyocytes (CMs), in the number of non-CM cells, and/or in the composition of the extracellular matrix, although some research suggests that increased size of CMs is an important feature of LVH and necessary to differentiate LVH from other benign forms of cardiac enlargement.
Observations: Llamas et al. sought to determine whether the same genetic loci control the size of CMs and LV mass (LVM). They found that one major locus was linked to LVM in both male and female mice. However, loci linked to the size of CMs were clearly distinct and showed sex-specific linkage. Additionally, they determined that the parental origin of chromosome Y had strong effects on the size of CMs in male mice but did not affect LVM.
Significance: In addition to showing that genetic loci that increase the size of CMs are not necessarily linked to increases in LVM, these findings have important implications for other studies that manipulate genetics and evaluate cardiac phenotypes in C57BL/6J mice. Namely, because C57BL/6J mice are most commonly used for genetic manipulations, the origin of chromosome Y should be assessed when genetic manipulations affect phenotypes in a sex-specific fashion.
Generation of a constitutive Na+-dependent inward-rectifier current in rat adult atrial myocytes by overexpression of Kir3.4. Mintert E, Bösche LI, Rinne A, Timpert M, Kienitz MC, Pott L, Bender K. J Physiol (September 20, 2007); doi:10.1113/jphysiol.140772.2007.
Nominated by Michael Kotlikoff
Associate Editor, Journal of Physiology
Cornell University
mik7{at}cornell.edu
Question: How does Na+-dependent gating affect endogenous Kir3.1/Kir3.4 channels?
Background: G-protein-activated inwardly rectifying potassium channels comprised of Kir3.x subunits are regulated by numerous mechanisms, including intracellular Na+ concentrations. Na+ regulates these channels via two distinct mechanisms. Na+ has been shown to directly activate Kir3 channels by binding to aspartate residues in the COOH terminus of Kir3.x subunits. Na+ also promotes the dissociation of G
GDP or rearrangement of Gβ
, which in turn affects gating kinetics of Kir3 channels.
Observations: In this study, Mintert et al. sought to determine how Na+-dependent gating affects endogenous Kir3.1/Kir3.4 channels in mammalian atrial myocytes. They found that Na+ had no effect on basal and receptor-evoked current carried by endogenous Kir3.x channels in rat atrial myocytes. However, when Kir3.4 was overexpressed in myocytes, there was robust activation of a basal inwardly rectifying current (Ibir) by Na+.
Significance: These results suggest that Na+ does not regulate cardiac Kir3 channels in atrial myocytes under normal physiological conditions. In addition, these data provide further support for the idea that Ibir is a homotetrameric Kir3.4 channel current with unique regulatory and pharmacological properties. This may have relevance to understanding the pathology associated with atrial fibrillation, because Ibir has some of the same properties as the basal current described in atrial myocytes from an animal model of atrial fibrillation.
A functional insulin-like growth factor receptor is not necessary for load-induced skeletal muscle hypertrophy. Spangenburg EE, Leroith D, Ward CW, Bodine SC. J Physiol (November 1, 2007); doi:10.1113/jphysiol.141507.2007.
Nominated by Michael Kjaer
Associate Editor, Journal of Physiology
University of Copenhagen
m.kjaer{at}mfi.ku.dk
Question: Is the insulin-like growth factor I (IGF-I) system necessary for load-induced skeletal muscle hypertrophy?
Background: When a mechanical load is applied to skeletal muscle, there is a myriad of signaling pathways activated that ultimately lead to an increase in muscle mass. One such pathway involves IGF-I, which is elevated at both the mRNA and protein levels in response to mechanical load increases. Although several studies have demonstrated the anabolic effects of IGF-I when applied exogenously, none have established the endogenous IGF-I system as a key factor for initiation of the growth response following a chronic mechanical load.
Observations: Using a functional overload (FO) model, Spangenburg et al. induced skeletal muscle hypertrophy in the plantaris muscle of wild-type (WT) and dominant negative IGF-I receptor (MKR) mice, which lack the ability to utilize endogenous IGF-I. Although the plantaris muscle mass was initially 11% greater in WT compared with MKR mice, both showed a significant increase in mass after 7 and 35 days of FO. At no point was the degree of hypertrophy significantly different between WT and MKR mice.
Significance: In contrast to what may have been predicted from the available data, increased mechanical load appears to be able to induce muscle hypertrophy independent of the IGF-I system. However, the authors did demonstrate that the Akt/mTOR signaling pathway, which is thought to be necessary for the induction of muscle growth, was activated in both WT and MKR mice. Hence, further work is needed to identify the upstream mechanism responsible for Akt-mediated signaling.
Orai1 mutations alter ion permeation and Ca2+-dependent fast inactivation of CRAC channels: evidence for coupling of permeation and gating.
Yamashita M, Navarro-Borelly L, McNally BA, Prakriya M. J Gen Physiol 130: 525–540, 2007.
Nominated by Angus Nairn
Associate Editor, Journal of General Physiology
Yale University
angus.nairn{at}yale.edu
Question: What can be learned about the calcium-released activated Ca2+ (CRAC) channel pore properties by mutating the pore-forming subunits of the channel?
Background: CRAC channels are store-operated channels (SOCs) that mediate the influx of Ca2+ when endoplasmic reticulum Ca2+ is depleted. Recently, the Orai family of proteins has been implicated as the pore-forming subunits of SOCs. However, many of the details surrounding the ion permeation and regulation of CRAC channel gating are not well understood.
Observations: Yamashita et al. determined that the biophysical properties of Orai1 correspond closely to native CRAC channels, suggesting that Orai1 is a key subunit of the CRAC channel pore. Pore mutations were found to change many properties of CRAC channels, including ion selectivity, block, and channel gating. A key result of this study is the finding that the low permeability of CRAC channels for Cs+ arises from stearic inhibition to Cs+ permeation from an unusually narrow pore. Additionally, mutations that alter Ca2+ and Cs+ permeability also strongly diminish Ca2+-mediated fast inactivation, suggesting that channel gating is coupled to ion permeation.
Significance: This is one of the first papers describing the biophysical properties of the Orai1 channel and the effects of "pore" mutations on permeation, selectivity, block, and gating. These findings are important because they provide novel insights into the process of fast inactivation, and thus Ca2+ regulation, of this important class of channels. From their novel findings, the authors propose that the structural elements involved in ion permeation overlap with those involved in the gating of CRAC channels.
Intergenic transcription and developmental regulation of cardiac myosin heavy chain genes. Haddad F, Qin AX, Bodell PW, Jiang W, Giger JM, Baldwin KM. Am J Physiol Heart Circ Physiol (November 2, 2007); doi:10.1152/ajp-heart.01125.2007.
Nominated by Alberto Nasjletti
Editor, American Journal of Physiology—Heart and Circulatory Physiology
New York Medical Center
alberto_nasjletti{at}nymc.edu
Question: How are cardiac myosin heavy chain (MHC) genes regulated during development?
Background: The MHC isoforms and β are encoded by two genes, which are located on the same chromosome. In cardiac tissue, the expression of MHC isoforms changes dramatically from β to during early rodent neonatal development. Thyroid hormone is a major regulator of MHC gene expression, which is thought to occur primarily via transcriptional processes. However, the mechanism by which thyroid hormone induces this developmental shift is unknown.
Observations: Using novel technology, Haddad et al. analyzed RNA expression across the cardiac gene locus and discovered that the intergenic (IG) region between the two cardiac genes possess bidirectional transcriptional activity, which results in an antisense RNA product that is thought to exert an inhibitory effect on βMHC gene transcription. From the IG region, they also identified a sense transcription that occurs, resulting in the expression of a sense IG RNA that merges with the MHC pre-RNA. Both the sense and antisense IG RNAs were developmentally regulated and responsive to a hypothyroid state.
Significance: These results suggest that the regulation of cardiac MHC gene locus involves epigenetic processes and that the developmental regulation of the two cardiac MHC genes is the result of cooperative functional linkage between the two genes. Furthermore, the role of thyroid hormone in regulating the postnatal transition from β to was further defined. There are several pathophysiological states that are associated with a change in MHC gene expression, thus this work may be pertinent to elucidating a dysfunctional mechanism associated with certain diseases.
Tarantula toxins interact with voltage sensors within lipid membranes.
Milescu M, Vobecky J, Roh SH, Kim SH, Jung HJ, Kim JI, Swartz KJ. J Gen Physiol 130: 497–511, 2007.
Nominated by Lawrence Palmer
Associate Editor, Journal of General Physiology
Cornell University
lgpal{at}med.cornell.edu
Question: How do toxins inhibit voltage-activated potassium (KV) channels?
Background: Voltage-gated ion channels, which are activated by changes in electrical potential, have a pore domain and four surrounding voltage-sensing domains. In addition, a voltage-sensor paddle is hypothesized to move at the protein-lipid interface in response to changes in membrane potential. Toxins from venomous creatures are known to partition into membranes, but whether this is sufficient to alter the activity of KV channels or the toxins have to directly interact with the voltage-sensor paddle is unknown.
Observations: In this report, Milescu et al. explored whether tarantula toxins like hanatoxin and SGTx1 inhibit KV channels by interacting with paddle motifs within the membrane. Although the toxins were found to partition into membranes, the toxin-membrane interaction was not sufficient to inhibit KV channels. They also identified regions of the toxin involved in binding to the paddle motif and those important for interacting with membranes.
Significance: These findings suggest that direct protein-protein interactions are involved in the inhibitory mechanism of the toxins and support the idea that toxin-channel interactions occur in the bilayer and that the voltage-sensor paddle motif moves at the interface where the channel meets the surrounding lipid membrane. In fact, the authors propose that the toxin, paddle region, and lipids form a trimolecular complex. This provides at least some insight into the structural basis of voltage sensing in KV channels.
Voltage-dependent dynamic FRET signals from the transverse tubules in mammalian skeletal muscle fibers.
Difranco M, Capote J, Quiñonez M, Vergara JL. J Gen Physiol 130: 581–600, 2007.
Nominated by Edward Pugh
Associate Editor, Journal of General Physiology
University of Pennsylvania
pugh{at}mail.med.upenn.edu
Question: Can a novel hybrid fluorescence resonance energy transfer (FRET) system be developed to follow changes in membrane potential?
Background: A transverse tubule (T-tubule) is a deep invagination of the plasma membrane found in skeletal and cardiac muscle cells that allow depolarization of the membrane to quickly penetrate to the interior of the cell. FRET, which is used to measure intra- and intermolecular distances between donor and acceptor fluorophores, was exploited to design a method to measure transmembrane potential in the T-tubule system and surface membranes of skeletal muscle fibers.
Observations: DiFranco and his colleagues performed experiments using recombinant fluorescent indicators to asses the dynamics of the membrane potential in the tubular system membrane of murine skeletal muscle. Although this approach has been previously introduced by others, this is the first time that it is used for measuring the membrane potential in a cellular compartment (the tubular system) that can not be accessed using standard electrophysiological techniques.
Significance: The current work is an impressive biophysical analysis of the changes in donor and acceptor fluorescence in relation to charge movement across the membrane studied in isolated muscle fibers by voltage clamp. A key advantage of the approach used in these studies may be that the donor could potentially be fused to proteins that are targeted to specific membrane compartments.
Metabolic homeostasis in mice with disrupted Clock gene expression in peripheral tissues.
Kennaway DJ, Owens JA, Voultsios A, Boden MJ, Varcoe TJ. Am J Physiol Regul Integr Comp Physiol 293: R1528–R1537, 2007.
Nominated by Curt Sigmund
Editor, American Journal of Physiology—Regulatroy, Integrative and Comparative Physiology
University of Iowa
curt-sigmund{at}uiowa.edu
Question: Does arrhythmic Clock gene expression in peripheral tissues contribute to metabolic abnormalities?
Background: Inherent biological rhythms control or initiate various biological processes, which are linked to the cycle of days. Interestingly, the abnormal rhythmicity shift workers are subjected to may be related to a twofold higher incidence of diabetes and 40% excess risk of cardiovascular disease compared with day workers. Kennaway et al. sought to determine whether selective arrhythmic expression of the Clock gene, a gene responsible for cellular rhythmicity, in peripheral tissues underlies the metabolic syndrome observed in shift workers.
Observations: Kennaway and colleagues developed a Clock mutant that retained central rhythmicity but displayed arrhythmic gene expression in the liver and skeletal muscle. These mutants showed impaired glucose tolerance and impaired insulin secretion. In addition, the mutants had altered gene expression of molecular determinants of metabolic homeostasis in liver and skeletal muscle.
Significance: Adding to the observations of recent studies that have shown that persistent phase shifting of the light/dark cycle disrupts rhythmicity in peripheral tissue clock-gene expression, these findings provide evidence that peripheral tissue clock-gene expression has an important role in metabolic homeostasis and may be responsible for the metabolic abnormalities observed in shift workers. Although the genetic background of an individual is important, circadian rhythm disruption may play a role in determining the severity of the metabolic impairment.
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