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PubMed1977

Inactivation of the sodium channel. I. Sodium current experiments.

Inactivation of sodium conductance has been studied in squid axons with voltage clamp techniques and with the enzyme pronase which selectively destroys inactivation. Comparison of the sodium current before and after pronase treatment shows a lag of several hundred microseconds in the onset of inactivation after depolarization. This lag can of several hundred microseconds in the onset of inactivation after polarization. This lag can also be demonstrated with double-pulse experiments. When the membrane potential is hyperpolarized to -140 mV before depolarization, both activation and inactivation are delayed. These findings suggest that inactivation occurs only after activation are delayed. These findings suggest that inactivation occurs only after activation; i.e. that the channels must open before they can inactivate. The time constant of inactivation measured with two pulses (tau(c)) is the same as the one measured from the decay of the sodium current during a single pulse (tau(h)). For large depolarizations, steady-state inactivation becomes more incomplete as voltage increases; but it is relatively complete and appears independent of voltage when determined with a two- pulse method. This result confirms the existence of a second open state for Na channels, as proposed by Chandler and Meves (1970. J. Physiol. [Lond.]. 211:653-678). The time constant of recovery from inactivation is voltage dependent and decreases as the membrane potential is made more negative. A model for Na channels is presented which has voltage-dependent transitions between the closed and open states, and a voltage-independent transition between the open and the inactivated state. In this model the voltage dependence of inactivation is a consequence of coupling to the activation process.

Action Potentials↗
PubMed1975

An essential ionized acid group in sodium channels.

Several recent experiments demonstrate the presence of an essential negatively charged acid group within sodium channels. Sodium permeability titrates away at low pH as if controlled by an acid with a voltage-dependent apparent pKa in the range between 5 and 6. The alkali ion permeability sequence of the channel is best explained by interactions between the cations and a strong negative charge in the channel. Block of sodium currents by a variety of metal and organic cations again points to a cation-coordinating site in the channel. The "blocking cations" and protons also oppose the bindings of tetrodotoxin and saxitoxin. The negative charge in the channel seems to be essential in selecting appropriate cations and in lowering their activation energy for permeation. The same charge seems to form part of the toxin receptor. At present this charged group is the chemical group known to be associated with sodium channels.--Hille B. An essential ionized acid group in sodium channels.

Binding Sites↗
PubMed1979

A pharmacological approach to the structure of sodium channels in myelinated axons.

Figure 6 summarizes the present state of our knowledge on the sodium channel in myelinated nerve fibers. Two sites have been discussed in detail: a metal cation binding site accessible by tetrodotoxin and saxitoxin from the outside surface only; and a second site accessible from the inside surface with which local anesthetics combine. Hydrogen ions gain access to this region of the sodium channel (and hence determine the relative local concentration of protonated drug) more readily from the extracellular fluid than from the axoplasm (Schwarz et al 1977). In addition, a variety of other sites have been mentioned, binding of drugs to which alters selectively the kinetics of opening and closing of the h and m gates. In myelinated nerve fibers these channels are packed tightly on the nodal membrane. The highest estimate for the sodium channel density in the mammalian node is 10,000 micron2. A re-evaluation of the effective nodal area, however, might reduce this value to 3000-5000/micron 2. This would still leave the nodal membrane rather crowded with sodium channels. Furthermore, the channel density would still be greater than the density of particles, sometimes believed to be sodium channels seen in freeze fracture studies (Rosenbluth 1976). One possibility for resolving this problem is that the units detected by X-ray inactivation (Levinson & Ellory 1973), and those seen in freeze-fracture studies (Rosenbluth 1976) represent not single sodium channels but groups of three. Catterall & Morrow (1978) in a comparison of the binding of saxitoxin and Leiurus sculpturatus scorpion toxin venom have concluded that there are three saxitoxin binding sites for each scorpion toxin binding site. On this basis, three saxitoxin molecules might act to block independently each of the three openings of the channels; while the the conformational change produced by the scorpion venom molecule would affect the inactivation process of all three channels.

Aconitine↗
PubMed1979

Selection of variant neuroblastoma clones with missing or altered sodium channels.

Neurotoxins that cause persistent activation of voltage-sensitive sodium channels are highly cytotoxic to electrically excitable neuroblastoma cells. These toxins were used as selective agents to isolate variant neuroblastoma clones with missing or altered sodium channels. Of ten resistant clones analyzed, seven lacked functional sodium channels and one had a specific 40-fold increase Kd for scorpion toxin and altered voltage dependence of scorpion toxin binding. The phenotypes of these cell clones were stable for more than 100 generations, indicating that they were the result of stable genetic change.

Animals↗
PubMed1978

Removal of sodium channel inactivation in squid giant axons by n-bromoacetamide.

The group-specific protein reagents, N-bromacetamide (NBA) and N-bromosuccinimide (NBS), modify sodium channel gating when perfused inside squid axons. The normal fast inactivation of sodium channels is irreversibly destroyed by 1 mM NBA or NBS near neutral pH. NBA apparently exhibits an all-or-none destruction of the inactivation process at the single channel level in a manner similar to internal perfusion of Pronase. Despite the complete removal of inactivation by NBA, the voltage-dependent activation of sodium channels remains unaltered as determined by (a) sodium current turn-on kinetics, (b) sodium tail current kinetics, (c) voltage dependence of steady-state activation, and (d) sensitivity of sodium channels to external calcium concentration. NBA and NBS, which can cleave peptide bonds only at tryptophan, tyrosine, or histidine residues and can oxidize sulfur-containing amino acids, were directly compared with regard to effects on sodium inactivation to several other reagents exhibiting overlapping protein reactivity spectra. N-acetylimidazole, a tyrosine-specific reagent, was the only other compound examined capable of partially mimicking NBA. Our results are consistent with recent models of sodium inactivation and support the involvement of a tyrosine residue in the inactivation gating structure of the sodium channel.

Acetamides↗
PubMed1979

[Unmasking of the fast sodium channel in less than 4 day old embryonic chicken heart by inhibitors of sodium inactivation].

Embryonic Chick hearts aged less than 4 days are not always sensitive to tetrodotoxin, an inhibitor of fast sodium channel. It is shown that in the most frequent cases, in which tetrodotoxin sensitivity is apparently absent, this sensitivity can be demonstrated after previous treatment by veratridine or by toxin II of androctonus australis Hector Scorpion venom. It is concluded that the fast tetrodotoxin-sensitive sodium channel is regularly present in the heart of Chick embryos aged 2 and 3 days, but most often in a permanently inactivated state.

Animals↗
PubMed1975

Binding of tetrodotoxin and saxitoxin to sodium channels.

A useful first step in any chemical characterization of the sodium channels in nerve membrane would clearly be the identification of some measurable property of the channel that does not depend on the intactness of the tissue. To this end, tetrodotoxin and saxitoxin, which bind specifically to sodium channels, have been triated and their binding to rabbit, lobster and garfish non-lyelinated nerve fibres examined. In each case, a component of the binding curve was found that saturated at concentrations of a few nanomolar. In addition, non-specific binding, indicated by a linear dependence of the amount bound on concentration, occurred. A solubilized membrane preparation from garfish nerve shows the same specific binding component as that of the intact nerve. The saturable component of binding seems to reflect the sodium channel density in nerve, and this is extremely small, being about 27/mum-2 in the rabbit nerve and as small as 6/mum-2 in the garfish nerve.

Animals↗
PubMed1977

Inactivation of sodium channels: second order kinetics in myelinated nerve.

1. Kinetics of inactivation of sodium channels in myelinated nerve from Rana pipiens were studied at 4.5 degrees C using the voltage clamp technique of Dodge & Frankenhaeuser (1958).2. Potassium currents were blocked by cutting the internodes in 20 mM-TEA-Cl + 100 mM-KCl and by adding 12 mM-TEA-Cl to the external Ringer. Leakage and capacitative currents were subtracted electronically.3. Kinetics of recovery from inactivation of the sodium channels were studied by inactivating the channels with a large depolarizing prepulse and allowing the channels to recover at different potentials; the extent of recovery was measured by applying a test pulse at various times after the prepulse.4. Kinetics of development of inactivation were studied by two different methods. The first was to measure the decay of sodium current under a maintained depolarization. The second method was to measure the decay of the peak sodium current in a test pulse as a function of time after the onset of a maintained depolarization. These two methods yielded similar results for the kinetics of inactivation development.5. Contrary to expectations of the Hodgkin-Huxley formalism, the time course of recovery from and development of inactivation is not strictly exponential. Rather, recovery from complete inactivation shows an initial delay which depends on recovery potentials. Development of inactivation at a fixed potential exhibits at least two exponentials.6. The steady-state inactivation curve h(infinity)(E) is asymmetrical and is fitted better by 1/[1+exp (A(1)E+B(1)) +exp (A(2)E+B(2))] than by 1/[1+exp (AE+B)].7. Most of the above kinetic observation on inactivation can be fitted by the following modification of the h system of the Hodgkin-Huxley formalism: [Formula: see text]8. In the analysis it was not necessary to modify the concept of two separate processes, activation and inactivation, governing the opening and closing of the sodium channels.

Animals↗
PubMed1979

Slow actions of hyperpolarization on sodium channels in the membrane of myelinated nerve.

The mean sodium current, I, and the variance of sodium current fluctuations, var, were measured in myelinated nerve during a depolarization to V = 40 mV applied from the resting potential (VH = 0) or from a hyperpolarizing holding potential VH = -28 mV. From I and var the relative variations in the number N and the conductance gamma of sodium channels following changes of the holding potential were calculated. Hyperpolarizing the membrane from VH = 0 to -28 mV increased N by a factor of 3.7, whereas gamma decreased by a factor of 0.53. These actions of holding potential on sodium channels develop slowly since 500 ms prepulses to 0 or -28 mV do not alter the values of N and gamma.

Animals↗
PubMed1978

A fully coupled transient excited state model for the sodium channel. II. Implications for action potential generation, threshold, repetitive firing, and accommodation.

The axon membrane is simulated by standard Hodgkin-Huxley leakage and potassium channels plus a coupled transient excited state kinetic scheme for the sodium channel. This scheme for the sodium channel is as proposed previously by the author. Simulations are presented showing the form of the action potential, threshold behavior, accommodation, and repetitive firing. It is seen that the form of the individual action potential, its all-or-none nature, and its refractory period are well simulated by this model, as they are by the standard Hodgkin-Huxley model. However, the model differs markedly from the Hodgkin-Huxley model with respect to repetitive firing and accommodation to stimulating currents of slowly rising intensity, in ways that are shown to be related to those features of the sodium inactivation which are anomalous to the H-H model. The tendency for repetitive firing is highly dependent on that parameter which primarily determines the existence of the inactivation shift in voltage clamp experiments, in such a way that the more pronounced the inactivation shift, the less the tendency for repetitive firing. The tendency for accommodation is highly dependent on that parameter which primarily determines the 'tauc-tauh' separation, in such a way that the greater the separation the greater the tendency for the membrane to accommodate without firing action potentials to a slowly rising current.

Action Potentials↗
PubMed1977

Current-voltage curve of sodium channels and concentration dependence of sodium permeability in frog skin.

1. The inward facing membranes of in vitro frog skin epithelium were depolarized with solutions of high K concentration. The electrical properties of the epithelium are then expected to be governed by the outward facing, Na-selective membrane.2. In this state, the transepithelial voltage (V) was clamped to zero and step-changes of Na activity in the outer solution ((Na)(o)) were performed with a fast-flow chamber at constant ionic strength, while the short-circuit current was recorded.3. At pre-selected times after a step-change of (Na)(o) the current response (I) to a fast voltage staircase was recorded. This procedure was repeated after blocking the Na channels with amiloride to obtain the current-voltage curve of transmembrane and paracellular shunt pathways. The current-voltage curve of the Na channels was computed by subtracting the shunt current from the total current.4. The instantaneous I(Na)-V curve thus obtained at a given (Na)(o) could easily be fitted with the constant field equation in the range between -50 and zero mV. This fit yielded approximate estimates of P(Na), the Na- permeability of the Na-selective membrane (at this (Na)(o)) and the cellular Na activity, (Na)(c). As residual properties of the serosal membrane were ignored the computed values are expected to underestimate the true ones.5. At constant (Na)(c), the steady-state value of 1/P(Na) increases linearly with (Na)(o). Error analysis and the effect of drugs show that the dependence is not due to the residual properties of the inward facing membranes but reflects the true behaviour of P(Na).6. The steady-state P(Na) at a given (Na)(o) is smaller than the transient P(Na) observed right after a stepwise increase of (Na)(o) to this value. The time constant of P(Na)-relaxation is in the order of seconds.7. In conclusion, Na transport through open Na-selective channels of the outward facing membrane of the stratum granulosum cells can be described as an electrodiffusion process which as such does not saturate with increasing (Na)(o). However, when added to the outer border of the membrane Na causes a decrease of P(Na) within several seconds. It is considered that binding of Na results in closure of Na channels.

Amiloride↗
PubMed1977

Density of sodium channels in mammalian myelinated nerve fibers and nature of the axonal membrane under the myelin sheath.

The density of sodium channels in mammalian myelinated fibers has been estimated from measurements of the binding of [3H]saxitoxin to rabbit sciatic nerve. Binding both to intact and to homogenized nerve consists of a linear, nonspecific, component and a saturable component that represents binding to the sodium channel. The maximum saturable binding capacity in intact nerve is 19.9 +/- 1.9 fmol-mg wet-1; the equilibrium dissociation constant, Kt, is 3.4 +/- 2.0 nM. Homogenization makes little difference, the maximum binding capacity being 19.9 +/- 1.5 fmol-mg wet-1 with Kt = 1.3 +/- 0.7 nM. These values correspond to a density of about 700,000 sodium channels per node--i.e., about 12,000 per mum2 of nodal membrane. From the difference between the values of maximum saturable binding capacity in intact and homogenized preparation, given the statistical uncertainty of their estimate, it seems that the internodal membrane can have no more than about 25 channels per mum2. The significance of these findings for saltatory conduction and in demyelinating disease is discussed.

Animals↗
PubMed1979

Binding of scorpion toxin to receptor sites associated with sodium channels in frog muscle. Correlation of voltage-dependent binding with activation.

Purified scorpion toxin (Leiurus quinquestriatus) slows inactivation of sodium channels in frog muscle at concentrations in the range of 17-170 nM. Mono[125I]iodo scorpion toxin binds to a single class of sites in frog sartorius muscle with a dissociation constant of 14 nM and a binding capacity of 13 fmol/mg wet weight. Specific binding is inhibited more than 90% by 3 microM sea anemone toxin II and by depolarization with 165 mM K+. Half-maximal inhibition of binding is observed on depolarization to -41 mV. The voltage dependence of scorpion toxin binding is correlated with the voltage dependence of activation of sodium channels. Removal of calcium from the bathing medium shifts both activation and inhibition of scorpion toxin binding to more negative membrane potentials. The results are considered in terms of the hypothesis that activation of sodium channels causes a conformational change in the scorpion toxin receptor site resulting in reduced affinity for scorpion toxin.

Animals↗
PubMed1979

Pharmacological properties of axonal sodium channels in the cockroach Periplaneta americana L. I. Selective block by synthetic saxitoxin.

Voltage-clamp experiments on isolated giant axons of the cockroach Periplaneta americana L. show that chemically synthesized saxitoxin specifically and reversibly blocks the transient inward sodium current without affecting the steady-state outward potassium current. From the concentration depending of sodium current suppression it is concluded that individual sodium channels are blocked by single molecules of synthetic saxitoxin which bind reversibly to part of the channel with a dissociation constant of 3.0 x 10(-9) M. Synthetic saxitoxin blocks sodium channels in cockroach axons at a lower concentration than tetrodotoxin. Sodium channel block by synthetic saxitoxin is more readily reversed than tetrodotoxin-induced block.

Animals↗
PubMed1979

Interactions between quaternary lidocaine, the sodium channel gates, and tetrodotoxin.

A voltage clamp technique was used to study sodium currents and gating currents in squid axons internally perfused with the membrane impermeant sodium channel blocker, QX-314. Block by QX-314 is strongly and reversibly enhanced if a train of depolarizing pulses precedes the measurement. The depolarization-induced block is antagonized by external sodium. This antagonism provides evidence that the blocking site for the drug lies inside the channel. Depolarization-induced block of sodium current by QX-314 is accompanied by nearly twofold reduction in gating charge movement. This reduction does not add to a depolarization-induced immobilization of gating charge normally present and believed to be associated with inactivation of sodium channels. Failure to act additively suggests that both, inactivation and QX-314, affect the same component of gating charge movement. Judged from gating current measurement, a drug-blocked channel is an inactivated channel. In the presence of external tetrodotoxin and internal QX-314, gating charge movement is always half its normal size regardless of conditioning, as it QX-314 is then permanently present in the channel.

Animals↗
PubMed1975

Negative surface charge near sodium channels of nerve: divalent ions, monovalent ions, and pH.

Evidence is given for a high density of negative surface charge near the sodium channel of myelinated nerve fibres. The voltage dependence of peak sodium permeability is measured in a voltage clamp. The object is to measure voltage shifts in sodium activation as the following external variables are varied: divalent cation concentration and type, monovalent concentration, and pH. With equimolar substitution of divalent ions the order of effectiveness for giving a positive shift is: Ba equals Sr less than Mg less than Ca less than Co approximately equal to Mn less than Ni less than Zn. A tenfold increase of concentration of any of these ions gives a shift of +20 to +25 mV. At low pH, the shift with a tenfold increase in Ca-2+ is much less than at normal pH, and conversely for high pH. Soulutions with no added divalent ions give a shift of minus 18 mV relative to 2 mM Ca-2+. Removal of 7/8 of the cations from the calcium-free solution gives a further shift of minue 35 mV. All shifts are explained quantitatively by assuming that changes in an external surface potential set up by fixed charges near the sodium channel produce the shifts. The model involves a diffuse double layer of counterions at the nerve surface and some binding of H+ions and divalent ions to the fixed charges. Three types of surface groups are postulated: (1) an acid pKa equals 2.88 charge density minus 0.9 nm- minus 2; (i) an acid pKa equals 4.58, charge density minus 0.58 nm- minus 2; (3) a base pKa equals 6.28, charge density +0.33 nm- minus 2. The two acid groups also bind Ca-2+ ions with a dissociation constant K equals 28 M. Reasonable agreement can also be obtained with a lower net surface charge density and stronger binding of divalent ions and H+ ions.

Animals↗
PubMed1979

Titration of sodium channel sites for hydrogen ion block and sensitized photochemical modification of lobster axons.

The pH dependence for sensitized photochemical block of sodium channels in lobster giant axons was determined and compared with direct channel block by protons. Isolated axons were studied in a double sucrose gap voltage clamp arrangement and the pH of the external bath was varied over the range 4.1--11.0. Irreversible photochemical block was achieved by illumination with visible light in the presence of eosin Y or acriding orange. The rate constant for photochemical block of sodium channels was depressed at both high and low pH relative to that at neutral pH, revealing the existence of two receptors involved in the process with pK values of 4.8 and 10.4. A direct reversible channel-blocking receptor titrates with a pK of 4.8, the same as one of the receptors involved in the photochemical block, and senses about 9% of the electric field as determined by a Woodhull analysis. Lowering the pH from 8.2 to 4.6 shifted the sodium conductance versus voltage relation in the depolarizing direction. It is proposed as a hypothesis that the low and high pK receptors are histidine imidazole and primary amino groups, photooxidation of which leads to channel block via cross-linking of channel proteins.

Animals↗
PubMed1979

[Comparative study of the action of procaine and benzocaine on normal and aconitine-modified sodium channels].

Ionic currents of normal and aconitine modified sodium channels of the Ranvier node membrane were measured under voltage clamp conditions. The experiments with local anesthetics in the external Ringer solution have showed that dissociation constant (Kdis) of normal channel-anesthetic complex for procaine is 0.27 + 0.03 mM, and for benzocaine is 0.68 +/- 0.04 mM. With aconitine modified channels, Kdis increases and becomes 1.32 +/- 0.5 mM and 1.52 +/- 0.3 mM for procaine and benzocaine, respectively. It is ascertained that the development of aconitine effect is inhibited by neutral benzocaine to a lesser extent than by procaine. It is shown that the aconitine effect cannot be reversed by a high concentration of anesthetic. Hence, it appears that aconitine and anesthetic receptors do not coincide.

Aconitine↗