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Journal of General Physiology

Jesús Aldair Canul-Sánchez, Ileana Hernández-Araiza, Enrique Hernández-García, Itzel Llorente, Sara L Morales-Lázaro, León D Islas, Tamara Rosenbaum
The TRPV1 ion channel is a membrane protein that is expressed in primary afferent nociceptors, where it is activated by a diverse array of stimuli. Our prior work has shown that this channel is activated by lysophosphatidic acid (LPA), an unsaturated lysophospholipid that is produced endogenously and released under certain pathophysiological conditions, resulting in the sensation of pain. Macroscopic currents activated by saturating concentrations of LPA applied to excised membrane patches are larger in magnitude than those activated by saturating concentrations of capsaicin, which causes near-maximal TRPV1 open probability...
November 8, 2018: Journal of General Physiology
Drew C Tilley, Juan M Angueyra, Kenneth S Eum, Heesoo Kim, Luke H Chao, Anthony W Peng, Jon T Sack
Allosteric ligands modulate protein activity by altering the energy landscape of conformational space in ligand-protein complexes. Here we investigate how ligand binding to a K+ channel's voltage sensor allosterically modulates opening of its K+ -conductive pore. The tarantula venom peptide guangxitoxin-1E (GxTx) binds to the voltage sensors of the rat voltage-gated K+ (Kv) channel Kv2.1 and acts as a partial inverse agonist. When bound to GxTx, Kv2.1 activates more slowly, deactivates more rapidly, and requires more positive voltage to reach the same K+ -conductance as the unbound channel...
November 5, 2018: Journal of General Physiology
Andrew L Harris
As the physiology of synapses began to be explored in the 1950s, it became clear that electrical communication between neurons could not always be explained by chemical transmission. Instead, careful studies pointed to a direct intercellular pathway of current flow and to the anatomical structure that was (eventually) called the gap junction. The mechanism of intercellular current flow was simple compared with chemical transmission, but the consequences of electrical signaling in excitable tissues were not...
November 2, 2018: Journal of General Physiology
Frank Zufall, Ana I Domingos
No abstract text is available yet for this article.
November 1, 2018: Journal of General Physiology
Kevin Michalski, Erik Henze, Phillip Nguyen, Patrick Lynch, Toshimitsu Kawate
Pannexins are a family of ATP release channels important for physiological and pathological processes like blood pressure regulation, epilepsy, and neuropathic pain. To study these important channels in vitro, voltage stimulation is the most common and convenient tool, particularly for pannexin 1 (Panx1). However, whether Panx1 is a voltage-gated channel remains controversial. Here, we carefully examine the effect of N-terminal modification on voltage-dependent Panx1 channel activity. Using a whole-cell patch-clamp recording technique, we demonstrate that both human and mouse Panx1, with their nativeN termini, give rise to voltage-dependent currents, but only at membrane potentials larger than +100 mV...
October 30, 2018: Journal of General Physiology
Caroline K Wang, Shawn M Lamothe, Alice W Wang, Runying Y Yang, Harley T Kurata
Ion channels encoded by KCNQ2-5 generate a prominent K+ conductance in the central nervous system, referred to as the M current, which is controlled by membrane voltage and PIP2. The KCNQ2-5 voltage-gated potassium channels are targeted by a variety of activating compounds that cause negative shifts in the voltage dependence of activation. The underlying pharmacology of these effects is of growing interest because of possible clinical applications. Recent studies have revealed multiple binding sites and mechanisms of action of KCNQ activators...
October 29, 2018: Journal of General Physiology
Brittany Williams, Françoise Haeseleer, Amy Lee
Ca2+ influx through Cav 1.4 L-type Ca2+ channels supports the sustained release of glutamate from photoreceptor synaptic terminals in darkness, a process that is critical for vision. Consistent with this role, Cav 1.4 exhibits weak Ca2+ -dependent inactivation (CDI)-a negative feedback regulation mediated by Ca2+ -bound calmodulin (CaM). CaM binds to a conserved IQ domain in the proximal C-terminal domain of Cav channels, but in Cav 1.4, a C-terminal modulatory domain (CTM) disrupts interactions with CaM. Exon 47 encodes a portion of the CTM and is deleted in a Cav 1...
October 24, 2018: Journal of General Physiology
Hiroko Takeuchi, Takashi Kurahashi
Odorants are detected by olfactory receptors on the sensory cilia of olfactory receptor cells (ORCs). These cylindrical cilia have a diameters of 100-200 nm, within which the components required for signal transduction by the adenylyl cyclase-cAMP system are located. The kinetics of odorant responses are determined by the lifetimes of active proteins as well as the production, diffusion, and extrusion/degradation of second messenger molecules (cAMP and Ca2+ ). However, there is limited information about the molecular kinetics of ORC responses, mostly because of the technical limitations involved in studying such narrow spaces and fine structures...
October 23, 2018: Journal of General Physiology
Michael A Kalwat, In Hyun Hwang, Jocelyn Macho, Magdalena G Grzemska, Jonathan Z Yang, Kathleen McGlynn, John B MacMillan, Melanie H Cobb
Modulators of insulin secretion could be used to treat diabetes and as tools to investigate β cell regulatory pathways in order to increase our understanding of pancreatic islet function. Toward this goal, we previously used an insulin-linked luciferase that is cosecreted with insulin in MIN6 β cells to perform a high-throughput screen of natural products for chronic effects on glucose-stimulated insulin secretion. In this study, using multiple phenotypic analyses, we found that one of the top natural product hits, chromomycin A2 (CMA2), potently inhibited insulin secretion by at least three potential mechanisms: disruption of Wnt signaling, interference of β cell gene expression, and partial suppression of Ca2+ influx...
October 23, 2018: Journal of General Physiology
Aditya Pisupati, Keith J Mickolajczyk, William Horton, Damian B van Rossum, Andriy Anishkin, Sree V Chintapalli, Xiaofan Li, Jose Chu-Luo, Gregory Busey, William O Hancock, Timothy Jegla
The Shaker-like family of voltage-gated K+ channels comprises four functionally independent gene subfamilies, Shaker (Kv1), Shab (Kv2), Shaw (Kv3), and Shal (Kv4), each of which regulates distinct aspects of neuronal excitability. Subfamily-specific assembly of tetrameric channels is mediated by the N-terminal T1 domain and segregates Kv1-4, allowing multiple channel types to function independently in the same cell. Typical Shaker-like Kv subunits can form functional channels as homotetramers, but a group of mammalian Kv2-related genes (Kv5...
October 15, 2018: Journal of General Physiology
Francisco Bezanilla
No abstract text is available yet for this article.
November 5, 2018: Journal of General Physiology
Marina A Kasimova, Aysenur Torun Yazici, Yevgen Yudin, Daniele Granata, Michael L Klein, Tibor Rohacs, Vincenzo Carnevale
The transient receptor potential channel vanilloid type 1 (TRPV1) is activated by a variety of endogenous and exogenous stimuli and is involved in nociception and body temperature regulation. Although the structure of TRPV1 has been experimentally determined in both the closed and open states, very little is known about its activation mechanism. In particular, the conformational changes that occur in the pore domain and result in ionic conduction have not yet been identified. Here we suggest a hypothetical molecular mechanism for TRPV1 activation, which involves rotation of a conserved asparagine in S6 from a position facing the S4-S5 linker toward the pore...
November 5, 2018: Journal of General Physiology
Daniel M Sigg, Hsueh-Kai Chang, Ru-Chi Shieh
Potassium-selective inward rectifier (Kir) channels are a class of membrane proteins necessary for maintaining stable resting membrane potentials, controlling excitability, and shaping the final repolarization of action potentials in excitable cells. In addition to the strong inward rectification of the ionic current caused by intracellular blockers, Kir2.1 channels possess "weak" inward rectification observed in inside-out patches after prolonged washout of intracellular blockers. The mechanisms underlying strong inward rectification have been attributed to voltage-dependent block by intracellular Mg2+ and polyamines; however, the mechanism responsible for weak rectification remains elusive...
November 5, 2018: Journal of General Physiology
Caitlin Sedwick
JGP study probes how nebulin affects muscle function.
November 5, 2018: Journal of General Physiology
Randy B Stockbridge
No abstract text is available yet for this article.
November 5, 2018: Journal of General Physiology
Sharona E Gordon
No abstract text is available yet for this article.
November 5, 2018: Journal of General Physiology
Tadashi Yamanishi, Hidehiko Koizumi, Marco A Navarro, Lorin S Milescu, Jeffrey C Smith
The rhythmic pattern of breathing depends on the pre-Bötzinger complex (preBötC) in the brainstem, a vital circuit that contains a population of neurons with intrinsic oscillatory bursting behavior. Here, we investigate the specific kinetic properties that enable voltage-gated sodium channels to establish oscillatory bursting in preBötC inspiratory neurons, which exhibit an unusually large persistent Na+ current (INaP ). We first characterize the kinetics of INaP in neonatal rat brainstem slices in vitro, using whole-cell patch-clamp and computational modeling, and then test the contribution of INaP to rhythmic bursting in live neurons, using the dynamic clamp technique...
November 5, 2018: Journal of General Physiology
Masataka Kawai, Tarek S Karam, Justin Kolb, Li Wang, Henk L Granzier
Nebulin (Neb) is associated with the thin filament in skeletal muscle cells, but its functions are not well understood. For this goal, we study skinned slow-twitch soleus muscle fibers from wild-type (Neb+ ) and conditional Neb knockout (Neb- ) mice. We characterize cross-bridge (CB) kinetics and the elementary steps of the CB cycle by sinusoidal analysis during full Ca2+ activation and observe that Neb increases active tension 1.9-fold, active stiffness 2.7-fold, and rigor stiffness 3.0-fold. The ratio of stiffness during activation and rigor states is 62% in Neb+ fibers and 68% in Neb- fibers...
November 5, 2018: Journal of General Physiology
Aaron Corbin-Leftwich, Hannah E Small, Helen H Robinson, Carlos A Villalba-Galea, Linda M Boland
Action potentials (APs) are the functional units of fast electrical signaling in excitable cells. The upstroke and downstroke of an AP is generated by the competing and asynchronous action of Na+ - and K+ -selective voltage-gated conductances. Although a mixture of voltage-gated channels has been long recognized to contribute to the generation and temporal characteristics of the AP, understanding how each of these proteins function and are regulated during electrical signaling remains the subject of intense research...
November 5, 2018: Journal of General Physiology
Jarred M Whitlock, Kuai Yu, Yuan Yuan Cui, H Criss Hartzell
Limb-girdle muscular dystrophy type 2L (LGMD2L) is a myopathy arising from mutations in ANO5 ; however, information about the contribution of ANO5 to muscle physiology is lacking. To explain the role of ANO5 in LGMD2L, we previously hypothesized that ANO5-mediated phospholipid scrambling facilitates cell-cell fusion of mononucleated muscle progenitor cells (MPCs), which is required for muscle repair. Here, we show that heterologous overexpression of ANO5 confers Ca2+ -dependent phospholipid scrambling to HEK-293 cells and that scrambling is associated with the simultaneous development of a nonselective ionic current...
November 5, 2018: Journal of General Physiology
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