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Journal of General Physiology

Priscilla See-Wai Yeung, Murali Prakriya
No abstract text is available yet for this article.
September 14, 2018: Journal of General Physiology
Caitlin Sedwick
New method predicts the molecular basis of membrane proteins' voltage sensitivity.
September 10, 2018: Journal of General Physiology
Wessel A C Burger, Patrick M Sexton, Arthur Christopoulos, David M Thal
Recent breakthroughs and developments in structural biology have led to a spate of crystal structures for G protein-coupled receptors (GPCRs). This is the case for the muscarinic acetylcholine receptors (mAChRs) where inactive-state structures for four of the five subtypes and two active-state structures for one subtype are available. These mAChR crystal structures have provided new insights into receptor mechanisms, dynamics, and allosteric modulation. This is highly relevant to the mAChRs given that these receptors are an exemplar model system for the study of GPCR allostery...
September 6, 2018: Journal of General Physiology
Michael C Yau, Robin Y Kim, Caroline K Wang, Jingru Li, Tarek Ammar, Runying Y Yang, Stephan A Pless, Harley T Kurata
Retigabine is an antiepileptic drug and the first voltage-gated potassium (Kv) channel opener to be approved for human therapeutic use. Retigabine is thought to interact with a conserved Trp side chain in the pore of KCNQ2-5 (Kv7.2-7.5) channels, causing a pronounced hyperpolarizing shift in the voltage dependence of activation. In this study, we investigate the functional stoichiometry of retigabine actions by manipulating the number of retigabine-sensitive subunits in concatenated KCNQ3 channel tetramers...
August 30, 2018: Journal of General Physiology
Alice W Wang, Michael C Yau, Caroline K Wang, Nazlee Sharmin, Runying Y Yang, Stephan A Pless, Harley T Kurata
KCNQ2-5 (Kv7.2-Kv7.5) channels are strongly influenced by an emerging class of small-molecule channel activators. Retigabine is the prototypical KCNQ activator that is thought to bind within the pore. It requires the presence of a Trp side chain that is conserved among retigabine-sensitive channels but absent in the retigabine-insensitive KCNQ1 subtype. Recent work has demonstrated that certain KCNQ openers are insensitive to mutations of this conserved Trp, and that their effects are instead abolished or attenuated by mutations in the voltage-sensing domain (VSD)...
August 30, 2018: Journal of General Physiology
Marina A Kasimova, Erik Lindahl, Lucie Delemotte
Voltage-sensitive membrane proteins are united by their ability to transform changes in membrane potential into mechanical work. They are responsible for a spectrum of physiological processes in living organisms, including electrical signaling and cell-cycle progression. Although the mechanism of voltage-sensing has been well characterized for some membrane proteins, including voltage-gated ion channels, even the location of the voltage-sensing elements remains unknown for others. Moreover, the detection of these elements by using experimental techniques is challenging because of the diversity of membrane proteins...
August 27, 2018: Journal of General Physiology
Heping Peace Cheng
No abstract text is available yet for this article.
August 27, 2018: Journal of General Physiology
Lucie Delemotte
No abstract text is available yet for this article.
August 24, 2018: Journal of General Physiology
Lei Yang, Lawrence G Palmer
The epithelial Na+ channel (ENaC) is a key transporter mediating and controlling Na+ reabsorption in many tight epithelia. A very high selectivity for Na+ over other cations, including K+ , is a hallmark of this channel. This selectivity greatly exceeds that of the closely related acid-sensing channels (ASICs). Here, we assess the roles of two regions of the ENaC transmembrane pore in the determination of cation selectivity. Mutations of conserved amino acids with acidic side chains near the cytoplasmic end of the pore diminish macroscopic currents but do not decrease the selectivity of the channel for Na+ versus K+ In the WT channel, voltage-dependent block of Na+ currents by K+ or guanidinium+ , neither of which have detectable conductance, suggests that these ions permeate only ∼20% of the transmembrane electric field...
August 22, 2018: Journal of General Physiology
Michelle Yen, Richard S Lewis
The binding of STIM1 to Orai1 controls the opening of store-operated CRAC channels as well as their extremely high Ca2+ selectivity. Although STIM1 dimers are known to bind directly to the cytosolic C termini of the six Orai1 subunits (SUs) that form the channel hexamer, the dependence of channel activation and selectivity on the number of occupied binding sites is not well understood. Here we address these questions using dimeric and hexameric Orai1 concatemers in which L273D mutations were introduced to inhibit STIM1 binding to specific Orai1 SUs...
August 17, 2018: Journal of General Physiology
Roman V Frolov, Esa-Ville Immonen, Paulus Saari, Päivi H Torkkeli, Hongxia Liu, Andrew S French
Plasticity is a crucial aspect of neuronal physiology essential for proper development and continuous functional optimization of neurons and neural circuits. Despite extensive studies of different visual systems, little is known about plasticity in mature microvillar photoreceptors. Here we investigate changes in electrophysiological properties and gene expression in photoreceptors of the adult cockroach, Periplaneta americana, after exposure to constant light (CL) or constant dark (CD) for several months. After CL, we observed a decrease in mean whole-cell capacitance, a proxy for cell membrane area, from 362 ± 160 to 157 ± 58 pF, and a decrease in absolute sensitivity...
August 16, 2018: Journal of General Physiology
Jing Li, Jared Ostmeyer, Luis G Cuello, Eduardo Perozo, Benoît Roux
C-type inactivation is a time-dependent process observed in many K+ channels whereby prolonged activation by an external stimulus leads to a reduction in ionic conduction. While C-type inactivation is thought to be a result of a constriction of the selectivity filter, the local dynamics of the process remain elusive. Here, we use molecular dynamics (MD) simulations of the KcsA channel to elucidate the nature of kinetically delayed activation/inactivation gating coupling. Microsecond-scale MD simulations based on the truncated form of the KcsA channel (C-terminal domain deleted) provide a first glimpse of the onset of C-type inactivation...
August 2, 2018: Journal of General Physiology
Jian Payandeh
No abstract text is available yet for this article.
September 3, 2018: Journal of General Physiology
Caitlin Sedwick
Tandem JGP studies investigate how propofol affects voltage-gated sodium channels.
September 3, 2018: Journal of General Physiology
Laurinda A Jaffe
No abstract text is available yet for this article.
September 3, 2018: Journal of General Physiology
Soumili Chatterjee, Rajan Vyas, Sreevatsa V Chalamalasetti, Indra D Sahu, Jérôme Clatot, Xiaoping Wan, Gary A Lorigan, Isabelle Deschênes, Sudha Chakrapani
Slow inactivation in voltage-gated sodium channels (NaV s) directly regulates the excitability of neurons, cardiac myocytes, and skeletal muscles. Although NaV slow inactivation appears to be conserved across phylogenies-from bacteria to humans-the structural basis for this mechanism remains unclear. Here, using site-directed labeling and EPR spectroscopic measurements of membrane-reconstituted prokaryotic NaV homologues, we characterize the conformational dynamics of the selectivity filter region in the conductive and slow-inactivated states to determine the molecular events underlying NaV gating...
September 3, 2018: Journal of General Physiology
Roman V Frolov
Photoreceptors in the compound eyes of most insect species express two functional types of depolarization-activated potassium currents: a transient A-type current (IA) and a sustained delayed rectifier current (IDR). The role of Shaker-dependent IA in Drosophila melanogaster photoreceptors was previously investigated by comparing intracellular recordings from Shaker and wild-type photoreceptors. Shaker channels were proposed to be involved in low-frequency signal amplification in dim light and reduction of the metabolic cost of information transfer...
September 3, 2018: Journal of General Physiology
Vinay Idikuda, Weihua Gao, Khade Grant, Zhuocheng Su, Qinglian Liu, Lei Zhou
Photochemically or metabolically generated singlet oxygen (1 O2 ) reacts broadly with macromolecules in the cell. Because of its short lifetime and working distance, 1 O2 holds potential as an effective and precise nanoscale tool for basic research and clinical practice. Here we investigate the modification of the spHCN channel that results from photochemically and chemically generated 1 O2 The spHCN channel shows strong voltage-dependent inactivation in the absence of cAMP. In the presence of photosensitizers, short laser pulses transform the gating properties of spHCN by abolishing inactivation and increasing the macroscopic current amplitude...
September 3, 2018: Journal of General Physiology
Yali Wang, Elaine Yang, Marta M Wells, Vasyl Bondarenko, Kellie Woll, Vincenzo Carnevale, Daniele Granata, Michael L Klein, Roderic G Eckenhoff, William P Dailey, Manuel Covarrubias, Pei Tang, Yan Xu
Voltage-gated sodium (NaV ) channels are important targets of general anesthetics, including the intravenous anesthetic propofol. Electrophysiology studies on the prokaryotic NaV channel NaChBac have demonstrated that propofol promotes channel activation and accelerates activation-coupled inactivation, but the molecular mechanisms of these effects are unclear. Here, guided by computational docking and molecular dynamics simulations, we predict several propofol-binding sites in NaChBac. We then strategically place small fluorinated probes at these putative binding sites and experimentally quantify the interaction strengths with a fluorinated propofol analogue, 4-fluoropropofol...
September 3, 2018: Journal of General Physiology
Elaine Yang, Daniele Granata, Roderic G Eckenhoff, Vincenzo Carnevale, Manuel Covarrubias
Propofol is widely used in the clinic for the induction and maintenance of general anesthesia. As with most general anesthetics, however, our understanding of its mechanism of action remains incomplete. Local and general anesthetics largely inhibit voltage-gated Na+ channels (Navs) by inducing an apparent stabilization of the inactivated state, associated in some instances with pore block. To determine the biophysical and molecular basis of propofol action in Navs, we investigated NaChBac and NavMs, two prokaryotic Navs with distinct voltage dependencies and gating kinetics, by whole-cell patch clamp electrophysiology in the absence and presence of propofol at clinically relevant concentrations (2-10 µM)...
September 3, 2018: Journal of General Physiology
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