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Journal of General Physiology

Zachery R Gregorich, Jitandrakumar R Patel, Wenxuan Cai, Ziqing Lin, Rachel Heurer, Daniel P Fitzsimons, Richard L Moss, Ying Ge
Enigma Homologue (ENH) is a component of the Z-disc, a structure that anchors actin filaments in the contractile unit of muscle, the sarcomere. Cardiac-specific ablation of ENH protein expression causes contractile dysfunction that ultimately culminates in dilated cardiomyopathy. However, whether ENH is involved in the regulation of myocardial contractility is unknown. To determine if ENH is required for the mechanical activity of cardiac muscle, we analyze muscle mechanics of isolated trabeculae from the hearts of ENH +/+ and ENH -/- mice...
January 14, 2019: Journal of General Physiology
Sushree Tripathy, Wenjun Zheng, Anthony Auerbach
Agonists turn on receptors because they bind more strongly to active (R*) versus resting (R) conformations of their target sites. Here, to explore how agonists activate neuromuscular acetylcholine receptors, we built homology models of R and R* neurotransmitter binding sites, docked ligands to those sites, ran molecular dynamics simulations to relax ("equilibrate") the structures, measured binding site structural parameters, and correlated them with experimental agonist binding energies. Each binding pocket is a pyramid formed by five aromatic amino acids and covered partially by loop C...
January 11, 2019: Journal of General Physiology
Tapan K Nayak, Ridhima Vij, Iva Bruhova, Jayasha Shandilya, Anthony Auerbach
Receptors alternate between resting↔active conformations that bind agonists with low↔high affinity. Here, we define a new agonist attribute, energy efficiency (η), as the fraction of ligand-binding energy converted into the mechanical work of the activation conformational change. η depends only on the resting/active agonist-binding energy ratio. In a plot of activation energy versus binding energy (an "efficiency" plot), the slope gives η and the y intercept gives the receptor's intrinsic activation energy (without agonists; ΔG0 )...
January 11, 2019: Journal of General Physiology
Niklas Ivarsson, C Mikael Mattsson, Arthur J Cheng, Joseph D Bruton, Björn Ekblom, Johanna T Lanner, Håkan Westerblad
Effective practices to improve skeletal muscle fatigue resistance are crucial for athletes as well as patients with dysfunctional muscles. To this end, it is important to identify the cellular signaling pathway that triggers mitochondrial biogenesis and thereby increases oxidative capacity and fatigue resistance in skeletal muscle fibers. Here, we test the hypothesis that the stress induced in skeletal muscle fibers by endurance exercise causes a reduction in the association of FK506-binding protein 12 (FKBP12) with ryanodine receptor 1 (RYR1)...
January 11, 2019: Journal of General Physiology
Juke S Lolkema, Dirk J Slotboom
With high-resolution structures available for many ion-coupled (secondary active) transporters, a major challenge for the field is to determine how coupling is accomplished. Knowledge of the kinetic mechanism of the transport reaction, which defines the binding order of substrate and co-ions, together with the sequence with which all relevant states are visited by the transporter, will help to reveal this coupling mechanism. Here, we derived general mathematical models that can be used to analyze data from steady-state transport measurements and show how kinetic mechanisms can be derived...
January 10, 2019: Journal of General Physiology
Caitlin Sedwick
JGP study examines how a mutation in KCNQ3 affects channel behavior.
January 9, 2019: Journal of General Physiology
Alistair G Fryatt, Sudad Dayl, Anastasios Stavrou, Ralf Schmid, Richard J Evans
The human P2X1 receptor (hP2X1R) is a trimeric ligand-gated ion channel opened by extracellular ATP. The intracellular amino and carboxyl termini play significant roles in determining the time-course and regulation of channel gating-for example, the C terminus regulates recovery from the desensitized state following agonist washout. This suggests that the intracellular regions of the channel have distinct structural features. Studies on the hP2X3R have shown that the intracellular regions associate to form a cytoplasmic cap in the open state of the channel...
January 9, 2019: Journal of General Physiology
Edward Y Shi, Christine L Yuan, Matthew T Sipple, Jayasri Srinivasan, Christopher P Ptak, Robert E Oswald, Linda M Nowak
Glutamate is released from presynaptic nerve terminals in the central nervous system (CNS) and spreads excitation by binding to and activating postsynaptic iGluRs. Of the potential glutamate targets, tetrameric AMPA receptors mediate fast, transient CNS signaling. Each of the four AMPA subunits in the receptor channel complex is capable of binding glutamate at its ligand-binding domains and transmitting the energy of activation to the pore domain. Homotetrameric AMPA receptor channels open in a stepwise manner, consistent with independent activation of individual subunits, and they exhibit complex kinetic behavior that manifests as temporal shifts between four different conductance levels...
January 8, 2019: Journal of General Physiology
Martin Kruse, Susy C Kohout, Bertil Hille
Voltage-sensing phosphatases (VSPs) cleave both 3- and 5-phosphates from inositol phospholipids in response to membrane depolarization. When low concentrations of Ciona intestinalis VSP are expressed in Xenopus laevis oocytes, the 5-phosphatase reaction can be observed during large membrane depolarizations. When higher concentrations are expressed, the 5-phosphatase activity is observed with smaller depolarizations, and the 3-phosphatase activity is revealed with strong depolarization. Here we ask whether this apparent induction of 3-phosphatase activity is attributable to the dimerization that has been reported when VSP is expressed at higher concentrations...
January 8, 2019: Journal of General Physiology
Elizabeth E L Lee, Francisco Bezanilla
Xenopus laevis oocytes are a widely used model system because of their capacity to translate exogenous mRNA, but their high intrinsic background fluorescence is a disadvantage for fluorescence recordings. Here, we developed two distinct methods for improving fluorescence recordings from oocytes. One was a pharmacological method in which a small-molecule salt-inducible kinase inhibitor was co-injected with the mRNA of interest to stimulate melanin production. We interrogated the oocytes using cut-open voltage clamp with simultaneous fluorescence recording and found that by increasing the amount of light-absorbing melanin in these oocytes, we decreased their intrinsic background fluorescence...
January 3, 2019: Journal of General Physiology
Sherif M Reda, Sampath K Gollapudi, Murali Chandra
Shifts in myosin heavy chain (MHC) isoforms in cardiac myocytes have been shown to alter cardiac muscle function not only in healthy developing hearts but also in diseased hearts. In guinea pig hearts, there is a large age-dependent shift in MHC isoforms from 80% α-MHC/20% β-MHC at 3 wk to 14% α-MHC/86% β-MHC at 11 wk. Because kinetic differences in α- and β-MHC cross-bridges (XBs) are known to impart different cooperative effects on thin filaments, we hypothesize here that differences in α- and β-MHC expression in guinea pig cardiac muscle impact sarcomere length (SL)-dependent contractile function...
January 2, 2019: Journal of General Physiology
Rocio K Finol-Urdaneta, Jeffrey R McArthur, Marcel P Goldschen-Ohm, Rachelle Gaudet, Denis B Tikhonov, Boris S Zhorov, Robert J French
Batrachotoxin (BTX), an alkaloid from skin secretions of dendrobatid frogs, causes paralysis and death by facilitating activation and inhibiting deactivation of eukaryotic voltage-gated sodium (Nav) channels, which underlie action potentials in nerve, muscle, and heart. A full understanding of the mechanism by which BTX modifies eukaryotic Nav gating awaits determination of high-resolution structures of functional toxin-channel complexes. Here, we investigate the action of BTX on the homotetrameric prokaryotic Nav channels NaChBac and NavSp1...
December 26, 2018: Journal of General Physiology
Rene Barro-Soria
One of the major factors known to cause neuronal hyperexcitability is malfunction of the potassium channels formed by KCNQ2 and KCNQ3. These channel subunits underlie the M current, which regulates neuronal excitability. Here, I investigate the molecular mechanisms by which epilepsy-associated mutations in the voltage sensor (S4) of KCNQ3 cause channel malfunction. Voltage clamp fluorometry reveals that the R230C mutation in KCNQ3 allows S4 movement but shifts the open/closed transition of the gate to very negative potentials...
December 21, 2018: Journal of General Physiology
Richard L Moss, Pieter P de Tombe, R John Solaro
No abstract text is available yet for this article.
December 21, 2018: Journal of General Physiology
Nicoletta Piroddi, E Rosalie Witjas-Paalberends, Claudia Ferrara, Cecilia Ferrantini, Giulia Vitale, Beatrice Scellini, Paul J M Wijnker, Vasco Sequiera, Dennis Dooijes, Cristobal Dos Remedios, Saskia Schlossarek, Man Ching Leung, Andrew Messer, Douglas G Ward, Annibale Biggeri, Chiara Tesi, Lucie Carrier, Charles S Redwood, Steven B Marston, Jolanda van der Velden, Corrado Poggesi
Hypertrophic cardiomyopathy (HCM) is a genetic form of left ventricular hypertrophy, primarily caused by mutations in sarcomere proteins. The cardiac remodeling that occurs as the disease develops can mask the pathogenic impact of the mutation. Here, to discriminate between mutation-induced and disease-related changes in myofilament function, we investigate the pathogenic mechanisms underlying HCM in a patient carrying a homozygous mutation (K280N) in the cardiac troponin T gene ( TNNT2 ), which results in 100% mutant cardiac troponin T...
December 21, 2018: Journal of General Physiology
Caitlin Sedwick
JGP paper explores how a mutated troponin T causes cardiac hypertrophy.
December 21, 2018: Journal of General Physiology
Jasmine Giles, Jitandrakumar R Patel, Adam Miller, Elizabeth Iverson, Daniel Fitzsimons, Richard L Moss
The loss of cardiac myosin binding protein C (cMyBP-C) results in left ventricular dilation, cardiac hypertrophy, and impaired ventricular function in both constitutive and conditional cMyBP-C knockout ( MYBPC3 null) mice. It remains unclear whether the structural and functional phenotypes expressed in the MYBPC3 null mouse are reversible, which is an important question, since reduced expression of cMyBP-C is an important cause of hypertrophic cardiomyopathy in humans. To investigate this question, we generated a cardiac-specific transgenic mouse model using a Tet-Off inducible system to permit the controlled expression of WT cMyBP-C on the MYBPC3 null background...
December 20, 2018: Journal of General Physiology
Rebecca E Slater, Joshua G Strom, Mei Methawasin, Martin Liss, Michael Gotthardt, Nancy Sweitzer, Henk L Granzier
Heart failure with preserved ejection fraction (HFpEF) is a complex syndrome characterized by a preserved ejection fraction but increased diastolic stiffness and abnormalities of filling. Although the prevalence of HFpEF is high and continues to rise, no effective therapies exist; however, the diabetic drug metformin has been associated with improved diastolic function in diabetic patients. Here we determine the therapeutic potential of metformin for improving diastolic function in a mouse model with HFpEF-like symptoms...
December 19, 2018: Journal of General Physiology
Marco A Navarro, Lorin S Milescu, Mirela Milescu
No abstract text is available yet for this article.
December 18, 2018: Journal of General Physiology
Vinay Idikuda, Weihua Gao, Zhuocheng Su, Qinglian Liu, Lei Zhou
Hyperpolarization-activated cyclic-nucleotide-modulated (HCN) channels are nonselective cation channels that regulate electrical activity in the heart and brain. Previous studies of mouse HCN2 (mHCN2) channels have shown that cAMP binds preferentially to and stabilizes these channels in the open state-a simple but elegant implementation of ligand-dependent gating. Distinct from mammalian isoforms, the sea urchin (spHCN) channel exhibits strong voltage-dependent inactivation in the absence of cAMP. Here, using fluorescently labeled cAMP molecules as a marker for cAMP binding, we report that the inactivated spHCN channel displays reduced cAMP binding compared with the closed channel...
December 12, 2018: Journal of General Physiology
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