scholarly journals Ionic selectivity, saturation, and block in sodium channels. A four-barrier model.

1975 ◽  
Vol 66 (5) ◽  
pp. 535-560 ◽  
Author(s):  
B Hille
Keyword(s):  
Dissociation Constants ◽  
Nerve Fibers ◽  
Na Channel ◽  
Rate Theory ◽  
Ionic Selectivity ◽  
Myelinated Nerve ◽  
Permeability Model ◽  
Zero Current ◽  
Ionic Fluxes ◽  
Barrier Model

Ionic fluxes in Na channels of myelinated axons show ionic competition, block, and deviations from simple flux independence. These phenomena are particularly evident when external Na+ ions are replaced by other permeant or impermeant ions. The observed currents require new flux equations not based on the concepts of free diffusion. A specific permeability model for the Na channel is developed from Eyring rate theory applied to a chain of saturable binding sites. There are four energy barriers in the pore and only one ion is allowed inside at a time. Deviations from independence arise from saturation. The model shows that ionic permeability ratios measured from zero-current potentials can differ from those measured from relative current amplitudes or conductances. The model can be fitted to experiments with various external sodium substitutes by varying only two parameters: For each ion the height of the major energy barrier (the selectivity filter) determines the biionic zero-current potential and the depth of the energy well (binding site) just external to that barrier then determines the current amplitudes. Voltage clamp measurements with myelinated nerve fibers are given showing numerous examples of deviations from independence in ionic fluxes. Strong blocks of ionic currents by guanidinium compounds and Tl+ ions are fitted by binding within the channel with apparent dissociation constants in the range 50-122 mM. A small block with high Na+ concentrations can be fitted by Na+ ion binding with a dissociation constant of 368 mM. The barrier model is given a molecular interpretation that includes stepwise dehydration of the permeating ion as it interacts with an ionized carboxylic acid.

scholarly journals The mechanosensitive ion channel TRAAK is localized to the mammalian node of Ranvier

eLife ◽  
2019 ◽  
Vol 8 ◽  
Author(s):  
Stephen G Brohawn ◽  
Weiwei Wang ◽  
Annie Handler ◽  
Ernest B Campbell ◽  
Jürgen R Schwarz ◽  
...  
Keyword(s):  
Action Potential ◽  
Polyclonal Antibodies ◽  
Node Of Ranvier ◽  
Nerve Fibers ◽  
K Channel ◽  
Resting Membrane Potential ◽  
Na Channel ◽  
Nodes Of Ranvier ◽  
Myelinated Nerve ◽  
Myelinated Nerve Fibers

TRAAK is a membrane tension-activated K+ channel that has been associated through behavioral studies to mechanical nociception. We used specific monoclonal antibodies in mice to show that TRAAK is localized exclusively to nodes of Ranvier, the action potential propagating elements of myelinated nerve fibers. Approximately 80 percent of myelinated nerve fibers throughout the central and peripheral nervous system contain TRAAK in what is likely an all-nodes or no-nodes per axon fashion. TRAAK is not observed at the axon initial segment where action potentials are first generated. We used polyclonal antibodies, the TRAAK inhibitor RU2 and node clamp amplifiers to demonstrate the presence and functional properties of TRAAK in rat nerve fibers. TRAAK contributes to the ‘leak’ K+ current in mammalian nerve fiber conduction by hyperpolarizing the resting membrane potential, thereby increasing Na+ channel availability for action potential propagation. We speculate on why nodes of Ranvier contain a mechanosensitive K+ channel.

scholarly journals Local anesthetics potently block a potential insensitive potassium channel in myelinated nerve.

1995 ◽  
Vol 105 (4) ◽  
pp. 485-505 ◽  
Author(s):  
M E Bräu ◽  
C Nau ◽  
G Hempelmann ◽  
W Vogel
Keyword(s):  
Local Anesthetics ◽  
Single Channel ◽  
Distribution Coefficients ◽  
Nerve Fibers ◽  
K Channel ◽  
Na Channel ◽  
Myelinated Nerve ◽  
Time Constants ◽  
Channel Inactivation ◽  
Ic50 Values

Effects of some local anesthetics were studied in patch clamp experiments on enzymatically demyelinated peripheral amphibian nerve fibers. Micromolar concentrations of external bupivacaine depolarized the excised membrane considerably. The flicker K+ channel was found to be the most sensitive ion channel to local anesthetics in this preparation. Half-maximum inhibiting concentrations (IC50) for extracellular application of bupivacaine, ropivacaine, etidocaine, mepivacaine, lidocaine, and QX-314 were 0.21, 4.2, 8.6, 56, 220, and > 10,000 microM, respectively. The corresponding concentration-effect curves could be fitted under the assumption of a 1:1 reaction. Application from the axoplasmic side resulted in clearly lower potencies with IC50 values of 2.1, 6.6, 16, 300, 1,200, and 1,250 microM, respectively. The log(IC50)-values of the local anesthetics linearly depended on the logarithm of their octanol:buffer distribution coefficients with two regression lines for the piperidine derivatives and the standard amino-amides indicating an inherently higher potency of the cyclic piperidine series. Amide-linked local anesthetics did not impair the amplitude of the single-channel current but prolonged the time of the channel to be in the closed state derived as time constants tau c from closed-time histograms. With etidocaine and lidocaine tau c was 133 and 7.2 ms, and proved to be independent of concentration. With the most potent bupivacaine time constants of wash in and wash out were 1.8 and 5.2 s for 600 nM bupivacaine. After lowering the extracellular pH from 7.4 to 6.6, externally applied bupivacaine showed a reduced potency, whereas at higher pH of 8.2 the block was slightly enhanced. Intracellular pH of 6.4, 7.2, 8.0 had almost no effect on internal bupivacaine block. It is concluded that local anesthetics block the flicker K+ channel by impeding its gating but not its conductance. The slow blocker bupivacaine and the fast blocker lidocaine compete for the same receptor. Lipophilic interactions are of importance for blockade but besides a hydrophobic pathway, there exists also a hydrophilic pathway to the binding site which could only be reached from the cytoplasmic side of the membrane. Under physiological conditions, blockade of the flicker K+ channel which is more sensitive to bupivacaine than the Na+ channel might lead via membrane depolarization and the resulting sodium channel inactivation to a pronounced block of conduction in thin fibers.

HISTOMETRIC AND ULTRASTRUCTURAL ORGANIZATION OF THE NERVIMUSCULAR TERMINALS OF SKELETAL MUSCLES AT A HYPOKINESIA

2019 ◽  
pp. 55-63
Author(s):  
Z. M. Yaschyshyn ◽  
S. L. Popel
Keyword(s):  
Skeletal Muscles ◽  
Structural Adjustment ◽  
Muscle Fibers ◽  
Electron Microscopic Examination ◽  
Nerve Fibers ◽  
Ultrastructural Changes ◽  
Ultrastructural Organization ◽  
Electron Microscopic ◽  
Myelinated Nerve ◽  
Male Wistar Rats

The aim: to study the dynamics of histological and ultrastructural changes in muscle fibers and their neuromuscular endings under conditions of prolonged hypokinesia at different stages of ontogenesis. Methods. Studied skeletal muscles and their peripheral nervous apparatus of laboratory male Wistar rats aged 30 to 270 days. The restriction of motor activity was carried out in special canister cells for 30, 60, 90, and 240 days (5 animals for each term). To determine the type of muscle fiber, the Nahlas histochemical method was used, the Kulchitsky method was used to detect myelinated nerve fibers, the Bilshovsky-Gros method and the electron microscopic method to identify neuromuscular endings. Results. The data of histological and electron microscopic examination of skeletal muscle fibers and their neuromuscular endings under conditions of prolonged hypokinesia indicate their regular restructuring during the development of muscles, the formation of their synapses and structures that are associated with them at different stages of ontogenesis. Conclusion. The study provides an in-depth understanding of the relative frequency and nature of the disturbance of the neuromuscular endings during prolonged hypokinesia and its effect on the dynamics of structural adjustment of individual types of muscle fibers in ontogenesis.

HISTOMETRIC AND ULTRASTRUCTURAL ORGANIZATION OF THE NERVIMUSCULAR TERMINALS OF SKELETAL MUSCLES AT A HYPOKINESIA

2019 ◽  
pp. 55-63
Author(s):  
Z. M. Yaschyshyn ◽  
S. L. Popel
Keyword(s):  
Skeletal Muscles ◽  
Structural Adjustment ◽  
Muscle Fibers ◽  
Electron Microscopic Examination ◽  
Nerve Fibers ◽  
Ultrastructural Changes ◽  
Ultrastructural Organization ◽  
Electron Microscopic ◽  
Myelinated Nerve ◽  
Male Wistar Rats

The aim: to study the dynamics of histological and ultrastructural changes in muscle fibers and their neuromuscular endings under conditions of prolonged hypokinesia at different stages of ontogenesis. Methods. Studied skeletal muscles and their peripheral nervous apparatus of laboratory male Wistar rats aged 30 to 270 days. The restriction of motor activity was carried out in special canister cells for 30, 60, 90, and 240 days (5 animals for each term). To determine the type of muscle fiber, the Nahlas histochemical method was used, the Kulchitsky method was used to detect myelinated nerve fibers, the Bilshovsky-Gros method and the electron microscopic method to identify neuromuscular endings. Results. The data of histological and electron microscopic examination of skeletal muscle fibers and their neuromuscular endings under conditions of prolonged hypokinesia indicate their regular restructuring during the development of muscles, the formation of their synapses and structures that are associated with them at different stages of ontogenesis. Conclusion. The study provides an in-depth understanding of the relative frequency and nature of the disturbance of the neuromuscular endings during prolonged hypokinesia and its effect on the dynamics of structural adjustment of individual types of muscle fibers in ontogenesis.

Whole cell and unitary amiloride-sensitive sodium currents in M-1 mouse cortical collecting duct cells

1996 ◽  
Vol 270 (4) ◽  
pp. C998-C1010 ◽  
Author(s):  
M. L. Chalfant ◽  
T. G. O'Brien ◽  
M. M. Civan
Keyword(s):  
Collecting Duct ◽  
Cell Permeability ◽  
Na Channel ◽  
Na Channels ◽  
Cortical Collecting Duct ◽  
Ionic Selectivity ◽  
Whole Cell ◽  
Duct Cells ◽  
Excised Patches ◽  
Collecting Duct Cells

Amiloride-sensitive whole cell currents have been reported in M-1 mouse cortical collecting duct cells (Korbmacher et al., J. Gen. Physiol. 102: 761-793, 1993). We have confirmed that amiloride inhibits the whole cell currents but not necessarily the measured whole cell currents. Anomalous responses were eliminated by removing external Na+ and/or introducing paraepithelial shunts. The amiloride-sensitive whole cell currents displayed Goldman rectification. The ionic selectivity sequence of the amiloride-sensitive conductance was Li+ > Na+ >> K+. Growth of M-1 cells on permeable supports increased the amiloride-sensitive whole cell permeability, compared with cells grown on plastic. Single amiloride-sensitive channels were observed, which conformed to the highly selective low-conductance amiloride-sensitive class [Na(5)] of epithelial Na+ channels. Hypotonic pretreatment markedly slowed run-down of channel activity. The gating of the M-1 Na+ channel in excised patches was complex. Open- and closed-state dwell-time distributions from patches that display one operative channel were best described with two or more exponential terms each. We conclude that 1) study of M-1 whole cell Na+ currents is facilitated by reducing the transepithelial potential to zero, 2) these M-1 currents reflect the operation of Na(5) channels, and 3) the Na+ channels display complex kinetics, involving > or = 2 open and > or = 2 closed states.

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