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Journal of General Physiology

Stephen C Cannon
No abstract text is available yet for this article.
November 14, 2017: Journal of General Physiology
Gerhard Meissner
Large-conductance Ca(2+) release channels known as ryanodine receptors (RyRs) mediate the release of Ca(2+) from an intracellular membrane compartment, the endo/sarcoplasmic reticulum. There are three mammalian RyR isoforms: RyR1 is present in skeletal muscle; RyR2 is in heart muscle; and RyR3 is expressed at low levels in many tissues including brain, smooth muscle, and slow-twitch skeletal muscle. RyRs form large protein complexes comprising four 560-kD RyR subunits, four ∼12-kD FK506-binding proteins, and various accessory proteins including calmodulin, protein kinases, and protein phosphatases...
November 9, 2017: Journal of General Physiology
Clarisse Fuster, Jimmy Perrot, Christine Berthier, Vincent Jacquemond, Pierre Charnet, Bruno Allard
Type 1 hypokalemic periodic paralysis (HypoPP1) is a poorly understood genetic neuromuscular disease characterized by episodic attacks of paralysis associated with low blood K(+) The vast majority of HypoPP1 mutations involve the replacement of an arginine by a neutral residue in one of the S4 segments of the α1 subunit of the skeletal muscle voltage-gated Ca(2+) channel, which is thought to generate a pathogenic gating pore current. The V876E HypoPP1 mutation has the peculiarity of being located in the S3 segment of domain III, rather than an S4 segment, raising the question of whether such a mutation induces a gating pore current...
November 7, 2017: Journal of General Physiology
Giovanni Gonzalez-Gutierrez, Yuhang Wang, Gisela D Cymes, Emad Tajkhorshid, Claudio Grosman
Remarkable advances have been made toward the structural characterization of ion channels in the last two decades. However, the unambiguous assignment of well-defined functional states to the obtained structural models has proved challenging. In the case of the superfamily of nicotinic-receptor channels (also referred to as pentameric ligand-gated ion channels [pLGICs]), for example, two different types of model of the open-channel conformation have been proposed on the basis of structures solved to resolutions better than 4...
October 31, 2017: Journal of General Physiology
Valentina Arkhipova, Albert Guskov, Dirk-Jan Slotboom
Crystal structures provide visual models of biological macromolecules, which are widely used to interpret data from functional studies and generate new mechanistic hypotheses. Because the quality of the collected x-ray diffraction data directly affects the reliability of the structural model, it is essential that the limitations of the models are carefully taken into account when making interpretations. Here we use the available crystal structures of members of the glutamate transporter family to illustrate the importance of inspecting the data that underlie the structural models...
October 31, 2017: Journal of General Physiology
Han-I Yeh, Yoshiro Sohma, Katja Conrath, Tzyh-Chang Hwang
Cystic fibrosis (CF) is a channelopathy caused by loss-of-function mutations of the cystic fibrosis transmembrane conductance regulator (CFTR) gene, which encodes a phosphorylation-activated and adenosine triphosphate (ATP)-gated chloride channel. In the past few years, high-throughput drug screening has successfully realized the first US Food and Drug Administration-approved therapy for CF, called ivacaftor (or VX-770). A more recent CFTR potentiator, GLPG1837 (N-(3-carbamoyl-5,5,7,7-tetramethyl-4,7-dihydro-5H-thieno[2,3-c]pyran-2-yl)-1H-pyrazole-3-carboxamide), has been shown to exhibit a higher efficacy than ivacaftor for the G551D mutation, yet the underlying mechanism of GLPG1837 remains unclear...
October 27, 2017: Journal of General Physiology
Osvaldo Alvarez, Ramon Latorre
In 1943, David Goldman published a seminal paper in The Journal of General Physiology that reported a concise expression for the membrane current as a function of ion concentrations and voltage. This body of work was, and still is, the theoretical pillar used to interpret the relationship between a cell's membrane potential and its external and/or internal ionic composition. Here, we describe from an historical perspective the theory underlying the constant-field equation and its application to membrane ion transport...
September 20, 2017: Journal of General Physiology
Caitlin Sedwick
New JGP study models how sinoatrial node pacemaker activity changes in aged hearts.
September 15, 2017: Journal of General Physiology
Meyer B Jackson
No abstract text is available yet for this article.
September 12, 2017: Journal of General Physiology
Joachim Behar, Yael Yaniv
Age-related deterioration of pacemaker function has been documented in mammals, including humans. In aged isolated sinoatrial node tissues and cells, reduction in the spontaneous action potential (AP) firing rate was associated with deterioration of intracellular and membrane mechanisms; however, their relative contribution to age-associated deficient pacemaker function is not known. Interestingly, pharmacological interventions that increase posttranslation modification signaling activities can restore the basal and maximal AP firing rate, but the identities of the protein targets responsible for AP firing rate restoration are not known...
September 8, 2017: Journal of General Physiology
Joan Pulupa, Manas Rachh, Michael D Tomasini, Joshua S Mincer, Sanford M Simon
The phenylalanine-glycine-repeat nucleoporins (FG-Nups), which occupy the lumen of the nuclear pore complex (NPC), are critical for transport between the nucleus and cytosol. Although NPCs differ in composition across species, they are largely conserved in organization and function. Transport through the pore is on the millisecond timescale. Here, to explore the dynamics of nucleoporins on this timescale, we use coarse-grained computational simulations. These simulations generate predictions that can be experimentally tested to distinguish between proposed mechanisms of transport...
September 8, 2017: Journal of General Physiology
Kevin P Bohannon, Mary A Bittner, Daniel A Lawrence, Daniel Axelrod, Ronald W Holz
A lumenal secretory granule protein, tissue plasminogen activator (tPA), greatly slows fusion pore dilation and thereby slows its own discharge. We investigated another outcome of the long-lived narrow fusion pore: the creation of a nanoscale chemical reaction chamber for granule contents in which the pH is suddenly neutralized upon fusion. Bovine adrenal chromaffin cells endogenously express both tPA and its primary protein inhibitor, plasminogen activator inhibitor 1 (PAI). We found by immunocytochemistry that tPA and PAI are co-packaged in the same secretory granule...
September 7, 2017: Journal of General Physiology
Parameswaran Hariharan, Lan Guan
The Na(+)-coupled melibiose symporter MelB, which can also be coupled to H(+) or Li(+) transport, is a prototype for the glycoside-pentoside-hexuronide:cation symporter family. Although the 3-D x-ray crystal structure of Salmonella typhimurium MelB (MelBSt) has been determined, the symport mechanisms for the obligatory coupled transport are not well understood. Here, we apply isothermal titration calorimetry to determine the energetics of Na(+) and melibiose binding to MelBSt, as well as protonation of this transporter...
November 6, 2017: Journal of General Physiology
Hans-Jürgen Apell
No abstract text is available yet for this article.
November 6, 2017: Journal of General Physiology
Caitlin Sedwick
New JGP study explores the thermodynamic cycle and cation preference of the sugar symporter MelB.
November 6, 2017: Journal of General Physiology
Dylan J Meyer, Craig Gatto, Pablo Artigas
Primary aldosteronism, a condition in which too much aldosterone is produced and that leads to hypertension, is often initiated by an aldosterone-producing adenoma within the zona glomerulosa of the adrenal cortex. Somatic mutations of ATP1A1, encoding the Na/K pump α1 subunit, have been found in these adenomas. It has been proposed that a passive inward current transported by several of these mutant pumps is a "gain-of-function" activity that produces membrane depolarization and concomitant increases in aldosterone production...
November 6, 2017: Journal of General Physiology
Yu Zhou, Huanghe Yang, Jianmin Cui, Christopher J Lingle
For those interested in the machinery of ion channel gating, the Ca(2+) and voltage-activated BK K(+) channel provides a compelling topic for investigation, by virtue of its dual allosteric regulation by both voltage and intracellular Ca(2+) and because its large-single channel conductance facilitates detailed kinetic analysis. Over the years, biophysical analyses have illuminated details of the allosteric regulation of BK channels and revealed insights into the mechanism of BK gating, e.g., inner cavity size and accessibility and voltage sensor-pore coupling...
November 6, 2017: Journal of General Physiology
Jon T Sack
Toxins are the poisonous products of organisms. Toxins serve vital defensive and offensive functions for those that harbor them: stinging scorpions, pesticidal plants, sanguinary snakes, fearless frogs, sliming snails, noxious newts, and smarting spiders. For physiologists, toxins are integral chemical tools that hijack life's fundamental processes with remarkable molecular specificity. Our understanding of electrophysiological phenomena has been transformed time and time again with the help of some terrifying toxins...
November 6, 2017: Journal of General Physiology
Juan Ferreira Gregorio, Germán Pequera, Carlo Manno, Eduardo Ríos, Gustavo Brum
In skeletal muscle, the four-helix voltage-sensing modules (VSMs) of CaV1.1 calcium channels simultaneously gate two Ca(2+) pathways: the CaV1.1 pore itself and the RyR1 calcium release channel in the sarcoplasmic reticulum. Here, to gain insight into the mechanism by which VSMs gate RyR1, we quantify intramembrane charge movement associated with VSM activation (sensing current) and gated Ca(2+) release flux in single muscle cells of mice and rats. As found for most four-helix VSMs, upon sustained depolarization, rodent VSMs lose the ability to activate Ca(2+) release channels opening; their properties change from a functionally capable mode, in which the mobile sensor charge is called charge 1, to an inactivated mode, charge 2, with a voltage dependence shifted toward more negative voltages...
November 6, 2017: Journal of General Physiology
Lawrence G Palmer
Epithelia define the boundaries of the body and often transfer solutes and water from outside to inside (absorption) or from inside to outside (secretion). Those processes involve dual plasma membranes with different transport components that interact with each other. Understanding those functions has entailed breaking down the problem to analyze properties of individual membranes (apical vs. basolateral) and individual transport proteins. It also requires understanding of how those components interact and how they are regulated...
October 2, 2017: Journal of General Physiology
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