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Journal of General Physiology

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https://www.readbyqxmd.com/read/30002162/biaryl-sulfonamide-motifs-up-or-down-regulate-ion-channel-activity-by-activating-voltage-sensors
#1
Sara I Liin, Per-Eric Lund, Johan E Larsson, Johan Brask, Björn Wallner, Fredrik Elinder
Voltage-gated ion channels are key molecules for the generation of cellular electrical excitability. Many pharmaceutical drugs target these channels by blocking their ion-conducting pore, but in many cases, channel-opening compounds would be more beneficial. Here, to search for new channel-opening compounds, we screen 18,000 compounds with high-throughput patch-clamp technology and find several potassium-channel openers that share a distinct biaryl-sulfonamide motif. Our data suggest that the negatively charged variants of these compounds bind to the top of the voltage-sensor domain, between transmembrane segments 3 and 4, to open the channel...
July 12, 2018: Journal of General Physiology
https://www.readbyqxmd.com/read/29997130/bridging-the-gap-toward-understanding-short-term-synaptic-plasticity
#2
Caitlin Sedwick
JGP study explores a new way to conceptualize an enduring neuronal mystery.
July 11, 2018: Journal of General Physiology
https://www.readbyqxmd.com/read/29980634/the-n-terminus-of-%C3%AE-enac-mediates-enac-cleavage-and-activation-by-furin
#3
Pradeep Kota, Martina Gentzsch, Yan L Dang, Richard C Boucher, M Jackson Stutts
Epithelial Na+ channels comprise three homologous subunits (α, β, and γ) that are regulated by alternative splicing and proteolytic cleavage. Here, we determine the basis of the reduced Na+ current (INa ) that results from expression of a previously identified, naturally occurring splice variant of the α subunit (α-ENaC), in which residues 34-82 are deleted (αΔ34-82 ). αΔ34-82 -ENaC expression with WT β and γ subunits in Xenopus oocytes produces reduced basal INa , which can largely be recovered by exogenous trypsin...
July 6, 2018: Journal of General Physiology
https://www.readbyqxmd.com/read/29980633/minimal-molecular-determinants-of-isoform-specific-differences-in-efficacy-in-the-hcn-channel-family
#4
Claudia P Alvarez-Baron, Vadim A Klenchin, Baron Chanda
Hyperpolarization-activated, cyclic nucleotide-gated (HCN) channels generate rhythmic activity in the heart and brain. Isoform-specific functional differences reflect the specializations required for the various roles that they play. Despite a high sequence and structural similarity, HCN isoforms differ greatly in their response to cyclic nucleotides. Cyclic AMP (cAMP) enhances the activity of HCN2 and HCN4 isoforms by shifting the voltage dependence of activation to more depolarized potentials, whereas HCN1 and HCN3 isoforms are practically insensitive to this ligand...
July 6, 2018: Journal of General Physiology
https://www.readbyqxmd.com/read/29970412/heat-resistant-action-potentials-require-ttx-resistant-sodium-channels-na-v-1-8-and-na-v-1-9
#5
Filip Touska, Brian Turnquist, Viktorie Vlachova, Peter W Reeh, Andreas Leffler, Katharina Zimmermann
Damage-sensing nociceptors in the skin provide an indispensable protective function thanks to their specialized ability to detect and transmit hot temperatures that would block or inflict irreversible damage in other mammalian neurons. Here we show that the exceptional capacity of skin C-fiber nociceptors to encode noxiously hot temperatures depends on two tetrodotoxin (TTX)-resistant sodium channel α-subunits: NaV 1.8 and NaV 1.9. We demonstrate that NaV 1.9, which is commonly considered an amplifier of subthreshold depolarizations at 20°C, undergoes a large gain of function when temperatures rise to the pain threshold...
July 3, 2018: Journal of General Physiology
https://www.readbyqxmd.com/read/29970411/no-voltage-change-at-skeletal-muscle-sr-membrane-during-ca-2-release-just-mermaids-on-acid
#6
Werner Melzer
Calcium ions control multiple physiological functions by binding to extracellular and intracellular targets. One of the best-studied Ca2+ -dependent functions is contraction of smooth and striated muscle tissue, which results from Ca2+ ligation to calmodulin and troponin C, respectively. Ca2+ signaling typically involves flux of the ion across membranes via specifically gated channel proteins. Because calcium ions are charged, they possess the ability to generate changes in the respective transmembrane voltage...
July 3, 2018: Journal of General Physiology
https://www.readbyqxmd.com/read/29970410/calnexin-revealed-as-an-ether-a-go-go-chaperone-by-getting-mutant-worms-up-and-going
#7
Jonathan T Pierce
The role of ion channels in cell excitability was first revealed in a series of voltage clamp experiments by Hodgkin and Huxley in the 1950s. However, it was not until the 1970s that patch-clamp recording ushered in a revolution that allowed physiologists to witness how ion channels flicker open and closed at angstrom scale and with microsecond resolution. The unexpectedly tight seal made by the patch pipette in the whole-cell configuration later allowed molecular biologists to suck up the insides of identified cells to unveil their unique molecular contents...
July 3, 2018: Journal of General Physiology
https://www.readbyqxmd.com/read/29959170/all-four-subunits-of-hcn2-channels-contribute-to-the-activation-gating-in-an-additive-but-intricate-manner
#8
Mallikarjuna Rao Sunkara, Tina Schwabe, Gunter Ehrlich, Jana Kusch, Klaus Benndorf
Hyperpolarization-activated cyclic nucleotide-modulated (HCN) channels are tetramers that elicit electrical rhythmicity in specialized brain neurons and cardiomyocytes. The channels are dually activated by voltage and binding of cyclic adenosine monophosphate (cAMP) to their four cyclic nucleotide-binding domains (CNBDs). Here we analyze the effects of cAMP binding to different concatemers of HCN2 channel subunits, each having a defined number of functional CNBDs. We show that each liganded CNBD promotes channel activation in an additive manner and that, in the special case of two functional CNBDs, functionality does not depend on the arrangement of the subunits...
June 29, 2018: Journal of General Physiology
https://www.readbyqxmd.com/read/29950400/a-two-step-docking-site-model-predicting-different-short-term-synaptic-plasticity-patterns
#9
Camila Pulido, Alain Marty
The strength of synaptic transmission varies during trains of presynaptic action potentials, notably because of the depletion of synaptic vesicles available for release. It has remained unclear why some synapses display depression over time, whereas others facilitate or show a facilitation and depression sequence. Here we compare the predictions of various synaptic models assuming that several docking/release sites are acting in parallel. These models show variation of docking site occupancy during trains of action potentials due to vesicular release and site replenishment, which give rise to changes in synaptic strength...
June 27, 2018: Journal of General Physiology
https://www.readbyqxmd.com/read/29950399/duplex-signaling-by-cam-and-stac3-enhances-ca-v-1-1-function-and-provides-insights-into-congenital-myopathy
#10
Jacqueline Niu, Wanjun Yang, David T Yue, Takanari Inoue, Manu Ben-Johny
CaV 1.1 is essential for skeletal muscle excitation-contraction coupling. Its functional expression is tuned by numerous regulatory proteins, yet underlying modulatory mechanisms remain ambiguous as CaV 1.1 fails to function in heterologous systems. In this study, by dissecting channel trafficking versus gating, we evaluated the requirements for functional CaV 1.1 in heterologous systems. Although coexpression of the auxiliary β subunit is sufficient for surface-membrane localization, this baseline trafficking is weak, and channels elicit a diminished open probability...
June 27, 2018: Journal of General Physiology
https://www.readbyqxmd.com/read/29941431/a-forward-genetic-screen-identifies-chaperone-cnx-1-as-a-conserved-biogenesis-regulator-of-erg-k-channels
#11
Xue Bai, Kai Li, Li Yao, Xin-Lei Kang, Shi-Qing Cai
The human ether-a-go-go-related gene (hERG) encodes a voltage-gated potassium channel that controls repolarization of cardiac action potentials. Accumulating evidence suggests that most disease-related hERG mutations reduce the function of the channel by disrupting protein biogenesis of the channel in the endoplasmic reticulum (ER). However, the molecular mechanism underlying the biogenesis of ERG K+ channels is largely unknown. By forward genetic screening, we identified an ER-located chaperone CNX-1, the worm homologue of mammalian chaperone Calnexin, as a critical regulator for the protein biogenesis of UNC-103, the ERG-type K+ channel in Caenorhabditis elegans Loss-of-function mutations of cnx-1 decreased the protein level and current density of the UNC-103 K+ channel and suppressed the behavioral defects caused by a gain-of-function mutation in unc-103 Moreover, CNX-1 facilitated tetrameric assembly of UNC-103 channel subunits in a liposome-assisted cell-free translation system...
June 25, 2018: Journal of General Physiology
https://www.readbyqxmd.com/read/29941430/gating-currents
#12
REVIEW
Francisco Bezanilla
Many membrane proteins sense the voltage across the membrane where they are inserted, and their function is affected by voltage changes. The voltage sensor consists of charges or dipoles that move in response to changes in the electric field, and their movement produces an electric current that has been called gating current. In the case of voltage-gated ion channels, the kinetic and steady-state properties of the gating charges provide information of conformational changes between closed states that are not visible when observing ionic currents only...
June 25, 2018: Journal of General Physiology
https://www.readbyqxmd.com/read/29930195/influences-find-a-friend
#13
Frances M Ashcroft
No abstract text is available yet for this article.
June 21, 2018: Journal of General Physiology
https://www.readbyqxmd.com/read/29921660/claudins-get-a-closer-look
#14
Caitlin Sedwick
JGP study examines claudin-15 ion selectivity and permeation.
June 19, 2018: Journal of General Physiology
https://www.readbyqxmd.com/read/29915162/molecular-determination-of-claudin-15-organization-and-channel-selectivity
#15
Priyanka Samanta, Yitang Wang, Shadi Fuladi, Jinjing Zou, Ye Li, Le Shen, Christopher Weber, Fatemeh Khalili-Araghi
Tight junctions are macromolecular structures that traverse the space between adjacent cells in epithelia and endothelia. Members of the claudin family are known to determine tight junction permeability in a charge- and size-selective manner. Here, we use molecular dynamics simulations to build and refine an atomic model of claudin-15 channels and study its transport properties. Our simulations indicate that claudin-15 forms well-defined channels for ions and molecules and otherwise "seals" the paracellular space through hydrophobic interactions...
June 18, 2018: Journal of General Physiology
https://www.readbyqxmd.com/read/29915161/known-structures-and-unknown-mechanisms-of-tmem16-scramblases-and-channels
#16
REVIEW
Maria E Falzone, Mattia Malvezzi, Byoung-Cheol Lee, Alessio Accardi
The TMEM16 family of membrane proteins is composed of both Ca2+ -gated Cl- channels and Ca2+ -dependent phospholipid scramblases. The functional diversity of TMEM16s underlies their involvement in numerous signal transduction pathways that connect changes in cytosolic Ca2+ levels to cellular signaling networks. Indeed, defects in the function of several TMEM16s cause a variety of genetic disorders, highlighting their fundamental pathophysiological importance. Here, we review how our mechanistic understanding of TMEM16 function has been shaped by recent functional and structural work...
June 18, 2018: Journal of General Physiology
https://www.readbyqxmd.com/read/29907600/external-k-dependence-of-strong-inward-rectifier-k-channel-conductance-is-caused-not-by-k-but-by-competitive-pore-blockade-by-external-na
#17
Keiko Ishihara
Strong inward rectifier K+ (sKir) channels determine the membrane potentials of many types of excitable and nonexcitable cells, most notably the resting potentials of cardiac myocytes. They show little outward current during membrane depolarization (i.e., strong inward rectification) because of the channel blockade by cytoplasmic polyamines, which depends on the deviation of the membrane potential from the K+ equilibrium potential ( V - E K ) when the extracellular K+ concentration ([K+ ]out ) is changed. Because their open - channel conductance is apparently proportional to the "square root" of [K+ ]out , increases/decreases in [K+ ]out enhance/diminish outward currents through sKir channels at membrane potentials near their reversal potential, which also affects, for example, the repolarization and action-potential duration of cardiac myocytes...
June 15, 2018: Journal of General Physiology
https://www.readbyqxmd.com/read/29903977/shear-elegance-a-novel-screen-uncovers-a-mechanosensitive-gpcr
#18
Ruby M Lam, Alexander T Chesler
No abstract text is available yet for this article.
June 14, 2018: Journal of General Physiology
https://www.readbyqxmd.com/read/29899059/tracking-the-sarcoplasmic-reticulum-membrane-voltage-in-muscle-with-a-fret-biosensor
#19
Colline Sanchez, Christine Berthier, Bruno Allard, Jimmy Perrot, Clément Bouvard, Hidekazu Tsutsui, Yasushi Okamura, Vincent Jacquemond
Ion channel activity in the plasma membrane of living cells generates voltage changes that are critical for numerous biological functions. The membrane of the endoplasmic/sarcoplasmic reticulum (ER/SR) is also endowed with ion channels, but whether changes in its voltage occur during cellular activity has remained ambiguous. This issue is critical for cell functions that depend on a Ca2+ flux across the reticulum membrane. This is the case for contraction of striated muscle, which is triggered by opening of ryanodine receptor Ca2+ release channels in the SR membrane in response to depolarization of the transverse invaginations of the plasma membrane (the t-tubules)...
June 13, 2018: Journal of General Physiology
https://www.readbyqxmd.com/read/29899058/a-privileged-role-for-neuronal-na-channels-in-regulating-ventricular-ca-2-and-arrhythmias
#20
DeAnalisa C Jones, Jingqi Q X Gong, Eric A Sobie
No abstract text is available yet for this article.
June 13, 2018: Journal of General Physiology
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