Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P50583 (asymmetrical)
 12,197 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Quaternary strychnine blocks sodium channels from the axoplasmic side, probably by insertion into the inner channel mouth. Block is strongly voltage dependent, being more pronounced in depolarized than in resting axons. Using potential steps as a means to modulate the level of block, we investigate strychnine effects on sodium and gating currents at +50 and -50 mV. We analyze our data in terms of the simplest possible model, wherein only an open channel may receive and retain a strychnine molecule. Our main findings are (a) block by strychnine and inactivation resemble each other and (b) block of sodium and gating currents by strychnine happen with closely similar time-courses. Our data support the hypothesis of Armstrong and Bezanilla (1977) wherein an endogenous blocking particle causes inactivation by inserting itself into the inner mouth of the sodium channel. Quaternary strychnine may act as an artificial substitute for the hypothetical endogenous blocking particle. Further, we suggest that at least 90% of the rapid asymmetrical displacement current in squid axons is sodium channel gating current, inasmuch as quaternary strychnine can block 90% of the displacement current simultaneously with sodium current.
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PMID:Block of sodium conductance and gating current in squid giant axons poisoned with quaternary strychnine. 23 69

The effect of aconitine on the asymmetrical displacement currents in Ranvier node membrane was studied. Aconitine evokes a shift of the charge displacement and time constant (tauon) membrane potential plots for the displacement currents in the direction of hyperpolarization by 50 mV. Maximum value of tauon in aconitine is twice as high as in norm and the reversal potentials for the displacement currents was estimated to be about--90 mV. The obtained results permit suggesting that the asymmetrical displacement current in its greater part is due to the operation of the gating mechanism of the sodium channel.
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PMID:[Effect of aconitine on asymmetric displacement currents in the membrane of a node of Ranvier]. 88 96

The effect of ultraviolet radiation on the asymmetrical displacement currents in the membrane of the node of Ranvier was measured and compared with the ultraviolet blocking of the sodium current. Ultraviolet radiation irreversibly reduced the peak sodium current and the charge displaced during a depolarizing test pulse, the relative reduction being independent of potential. The ratio of the ultraviolet sensitivities of the sodium and the asymmetrical displacement currents is 2.3+/- 0.2. This result suggests two independent identical gating particles per sodium channel in the membrane of myelinated nerve.
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PMID:Block of gating currents by ultraviolet radiation in the membrane of myelinated nerve. 98 22

A fast component of displacement current which accompanies the sodium channel gating current has been recorded from the membrane of the giant axon of the squid Loligo forbesii. This component is characterized by relaxation time constants typically shorter than 25 microseconds. The charge displaced accounts for about 10% (or 2 nC/cm2) of the total displacement charge attributed to voltage-dependent sodium channels. Using a low noise, wide-band voltage clamp system and specially designed voltage step protocols we could demonstrate that this component: (i) is not a recording artifact; (ii) is kinetically independent from the sodium channel activation and inactivation processes; (iii) can account for a significant fraction of the initial amplitude of recorded displacement current and (iv) has a steady state charge transfer which saturates for membrane potentials above +20 mV and below -100 mV. This component can be modelled as a single step transition using the Eyring-Boltzmann formalism with a quantal charge of 1 e- and an asymmetrical energy barrier. Furthermore, if it were associated with the squid sodium channel, our data would suggest one fast transition per channel. A possible role as a sodium channel activation trigger, which would still be consistent with kinetic independence, is discussed. Despite uncertainties about its origin, the property of kinetic independence allows subtraction of this component from the total displacement current to reveal a rising phase in the early time course of the remaining current. This will have to be taken into account when modelling the voltage-dependent sodium channel.
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PMID:The early phase of sodium channel gating current in the squid giant axon. Characteristics of a fast component of displacement charge movement. 132 30

1. Two mutants of the sodium channel II have been expressed in Xenopus oocytes and have been investigated using the patch-clamp technique. In mutant E387Q the glutamic acid at position 387 has been replaced by glutamine, and in mutant D384N the aspartic acid at position 384 has been replaced by asparagine. 2. Mutant E387Q, previously shown to be resistant to block by tetrodotoxin (Noda et al. 1989), has a single-channel conductance of 4 pS, that can be easily measured only using noise analysis. At variance with the wild-type, the open-channel current-voltage relationship of mutant E387Q is linear over a wide voltage range even under asymmetrical ionic conditions. 3. Mutant D384N has a very low permeability for any of the following ions: Cl-, Na+, K+, Li+, Rb+, Ca2+, Mg2+, NH+4, TMA+, TEA+. However, asymmetric charge movements similar to the gating currents of the Na(+)-selective wild-type are still observed. 4. These results suggest that residues E387 and D384 interact directly with the pathway of the ions permeating the open channel.
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PMID:Single point mutations of the sodium channel drastically reduce the pore permeability without preventing its gating. 166 Mar 94

The effect of the negatively charged ganglioside GD1a, one of the major brain gangliosides [H. Beitinger, W. Probst, R. Hilbig, H. Rahmann, Seasonal variability of sialo-glycoconjugates in the brain of the Djungarian hamster (Phodopus sungorus). Comp. Biochem. Physiol., B 86 (1987) 377-384] on the function of brain derived BTX-modified voltage-dependent sodium channel was studied using the planar lipid bilayer system. Bilayers were formed either with a mixture of neutral phospholipids (4 phosphoethanolamine (PE):1 phosphocholine (PC)) alone or with one containing 6% of the disialoganglioside GD1a. The permeation and activation properties of the channels were measured in the presence of symmetrical 200 mM NaCl. We found that the single channel conductance was not affected by GD1a, whereas the steady-state activation curve displayed a hyperpolarizing shift in the presence of GD1a. Since the lipid distribution in these membranes is symmetrical, then the GD1a effect on sodium channels may result either from an induction of channel conformational changes or from an asymmetrical interaction between the channel (extracellular vs. intracellular channel aspect) and GD1a. Regardless of the mechanism, the data indicate that differences in ganglioside content in neuronal cells may contribute to the previously observed sodium channel functional variability within (soma, dentritic, axon hillock) and between neuronal cells as well as to excitability changes in those physiological and pathological conditions where changes in the neuronal ganglioside content occur.
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PMID:Ganglioside GD1a increases the excitability of voltage-dependent sodium channels. 1534 62

Voltage clamp measurements reveal important insights into the activity of membrane ion channels. While conventional voltage clamp systems are available for laboratory studies, these instruments are generally unsuitable for more rugged operating environments. In this study, we present a non-invasive microfluidic voltage clamp system developed for the use under varying gravity levels. The core component is a multilayer microfluidic device that provides an immobilisation site for Xenopus laevis oocytes on an intermediate layer, and fluid and electrical connections from either side of the cell. The configuration that we term the asymmetrical transoocyte voltage clamp (ATOVC) also permits electrical access to the cytosol of the oocyte without physical introduction of electrodes by permeabilisation of a large region of the oocyte membrane so that a defined membrane patch can be voltage clamped. The constant low level air pressure applied to the oocyte ensures stable immobilisation, which is essential for keeping the leak resistance constant even under varying gravitational forces. The ease of oocyte mounting and immobilisation combined with the robustness and complete enclosure of the fluidics system allow the use of the ATOVC under extreme environmental conditions, without the need for intervention by a human operator. Results for oocytes over-expressing the epithelial sodium channel (ENaC) obtained under laboratory conditions as well as under conditions of micro- and hypergravity demonstrate the high reproducibility and stability of the ATOVC system under distinct mechanical scenarios.
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PMID:Microfluidic platform for electrophysiological studies on Xenopus laevis oocytes under varying gravity levels. 2187 12

Sodium channels are chief proteins involved in electrical signaling in the nervous system, enabling critical functions like heartbeat and brain activity. New high-resolution X-ray structures for bacterial sodium channels have created an opportunity to see how these proteins operate at the molecular level. An important challenge to overcome is establishing relationships between the structures and functions of mammalian and bacterial channels. Bacterial sodium channels are known to exhibit the main structural features of their mammalian counterparts, as well as several key functional characteristics, including selective ion conduction, voltage-dependent gating, pore-based inactivation and modulation by local anesthetic, antiarrhythmic and antiepileptic drugs. Simulations have begun to shed light on each of these features in the past few years. Despite deviations in selectivity signatures for bacterial and mammalian channels, simulations have uncovered the nature of the multiion conduction mechanism associated with Na(+) binding to a high-field strength site established by charged glutamate side chains. Simulations demonstrated a surprising level of flexibility of the protein, showing that these side chains are active participants in the permeation process. They have also uncovered changes in protein structure, leading to asymmetrical collapses of the activation gate that have been proposed to correspond to inactivated structures. These observations offer the potential to examine the mechanisms of state-dependent drug activity, focusing on pore-blocking and pore-based slow inactivation in bacterial channels, without the complexities of inactivation on multiple timescales seen in eukaryotic channels. Simulations have provided molecular views of the interactions of drugs, consistent with sites predicted in mammalian channels, as well as a wealth of other sites as potential new drug targets. In this chapter, we survey the new insights into sodium channel function that have emerged from studies of simpler bacterial channels, which provide an excellent learning platform, and promising avenues for mechanistic discovery and pharmacological development.
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PMID:Understanding Sodium Channel Function and Modulation Using Atomistic Simulations of Bacterial Channel Structures. 2758 84