Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0019829 (Hodgkin's disease)
 30,247 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Sodium currents, INa, were recorded from Xenopus laevis oocytes which had been injected with mRNA synthesized by in vitro transcription of the rat brain sodium channel II cDNA (Noda et al. 1986 a, b). Patch pipettes were used to apply depolarizing voltage steps and to record macroscopic sodium currents of between 50 and 750 pA from cell-attached patches of the oocyte membrane. With a combination of whole-cell and patch clamp recording, the properties of the implanted sodium channels could be studied in detail. They were analyzed according to the model of Hodgkin and Huxley (1952 a) assuming three activation gates. The activation of the sodium currents is characterized by an equilibrium potential of -29 mV and an apparent gating charge of 8.7 e0. At -64 mV half of the sodium currents were inactivated. From single-channel current recordings, an elementary sodium channel conductance of 19 pS and an average open time of 0.43 ms were obtained at -32 mV membrane potential and 16 degrees C. The single-channel and activation properties of rat brain sodium channel II are therefore comparable to those found in peripheral nerve and skeletal muscle, but inactivation occurs at less negative potentials. This could be a specific property of the brain sodium channels and may underlie the maintained inward sodium currents reported in brain neurones (French and Gage 1985).
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PMID:Patch clamp characterization of sodium channels expressed from rat brain cDNA. 243 40

1 The actions of the class I anti-arrythmic agent, disopyramide, on the ionic currents of the voltage-clamped squid axon have been investigated, by use of both extra-axonal and intra-axonal routes of application. 2 Extra-axonal application of 0.1 mM disopyramide produced no significant effects on the membrane currents. External disopyramide at 1.0 mM caused small, poorly reversible inhibition of both sodium and potassium currents. This block was use-dependent and was enhanced by use of test stimuli to more positive membrane potentials. 3 Intra-axonal application of 0.1 mM disopyramide caused a 40% reduction in the first-pulse sodium current (tonic block) and an additional use-dependent block. Analysis of first-pulse currents in terms of the Hodgkin-Huxley formalism indicated that the block resulted mainly from a reduction in the maximum available sodium conductance (gNa); there were no effects on the voltage dependence of the steady-state activation and inactivation parameters, m infinity and h infinity. 4 The use-dependent actions of disopyramide were investigated with a double voltage-clamp pulse protocol. The significant use-dependent effects of the drug were a further reduction in gNa and an increase in the time constant of inactivation (tau h). 5 Disopyramide appears to enter a blocking site in the sodium channel which is only readily accessible from the axoplasmic phase. Partition to the site depends on membrane voltage and on the state of the channel gates. Disopyramide binds at a significant rate to both open and inactivated forms of the sodium channel.
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PMID:The effects of external and internal application of disopyramide on the ionic currents of the squid giant axon. 244 1

Since the work of A. L. Hodgkin and A. F. Huxley (1952. J. Physiol. [Lond.].117:500-544) the squid giant axon has been considered the classical preparation for the study of voltage-dependent sodium and potassium channels. In this preparation much data have been gathered on macroscopic and gating currents but no single sodium channel data have been available. This paper reports patch clamp recording of single sodium channel events from the cut-open squid axon. It is shown that the single channel conductance in the absence of external divalent ions is approximately 14 pS, similar to sodium channels recorded from other preparations, and that their kinetic properties are consistent with previous results on gating and macroscopic currents obtained from the perfused squid axon preparation.
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PMID:Single sodium channels from the squid giant axon. 244 71

Lidocaine block of the cardiac sodium channel is believed to be primarily a function of channel state. For subthreshold potentials, block is limited to the inactivated state, whereas above threshold, block results from the combination of open- and inactivated-state block. Since, in the absence of drug, inactivation develops with time constants that vary from several hundred milliseconds to a few milliseconds as potential is varied from subthreshold to strongly depolarized levels, we would predict a similar voltage dependence of at least a fraction of block. Prior theoretical analyses from our laboratory suggest that there should be a direct parallel between blockade determined with a single pulse and trains of pulses. We tested these predictions by measuring the blockade of sodium current in cultured atrial myocytes during exposure to 80 microM lidocaine. We selected two test potentials for most of our studies, -80 mV, which was clearly in the subthreshold range of potentials, and -20 mV, which was close to the peak of the current-voltage curve. With single pulses of increasing duration, block developed with a single exponential time course and with time constants that decreased from 694 +/- 117 msec at -80 mV to 373 +/- 54 msec at -20 mV. In the absence of drug, inactivation developed with a time constant 176 +/- 17 at -80 mV and 2.9 +/- .5 msec at -20 mV. Despite the much slower onset of inactivation at -80 mV, no second-order delay in block development was observed. This suggests that at -80 mV block is occurring to a channel conformation that is accessed without delay rather than the classical inactivated state. We compared the kinetics of block during a single continuous pulse with trains of pulses at -20 mV. The rate of block onset was faster during the pulse trains, suggesting an element of "activated state" block. We computed shifts in apparent inactivation from observed steady-state blockade. The computed shifts agree well with those observed, indicating that shifts in apparent inactivation result largely from voltage-sensitive equilibrium blockade. The classical states described in the Hodgkin-Huxley formalism may be too restrictive to fully describe the voltage- and time-dependent block of cardiac sodium channels.
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PMID:Blockade of rabbit atrial sodium channels by lidocaine. Characterization of continuous and frequency-dependent blocking. 254 63

The probabilities m of the sodium activation gate being open are shown to fit experimentally-determined running integrals Qg of recordings of the colchicine-sensitive fraction of the asymmetry current, within the Hodgkin-Huxley framework that the gate could have only two conformations, open and closed. Using the Hodgkin-Huxley framework, we are obliged to assume that the transition velocities, alpha m and beta m, between the open and closed gates depend not only on membrane potentials V but also on the time after a potential step was externally applied. We introduce the following functions of alpha m and beta m. (sequence in text) where VH, td and tau p stand for holding potential, constant delay time of 10 microseconds, and transit time of the transition velocity of alpha m (or beta m) from its initial value alpha om (or beta om) to its final steady value alpha infinity m (or beta infinity m), respectively. The transit time tau p was found to be potential-dependent; typically it was 30 microseconds at -20 mV, and 100 microseconds at 20-40 mV. The values of alpha infinity m, alpha om, beta infinity m and beta om were found to be in reasonable agreement with those obtained by others, under the Hodgkin-Huxley assumption that the gate followed first-order kinetics. The requirement of new parameters, tau p and td, in the transition velocities was discussed in a relation to a membrane model where a voltage-receptor and a sodium channel macromolecule are spatially separated but functionally connected through underlying cytoskeletons (Matsumoto, 1984).
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PMID:Modified Hodgkin-Huxley gating kinetics of sodium activation in giant axons of squid (Doryteuthis bleekeri). 258 7

Sensory transduction at a primary receptor neuron yields a current that drives the generation of action potentials. Due to the inaccessibility of that current for direct measurements the analysis of sensory transduction requires the use of neuronal output functions that give an indirect measure for the "input" current, i.e. the current at the impulse initiating site. Three continuous neuronal output functions are investigated with respect to their ability to reconstruct the input current (i) the membrane potential recorded under sodium channel block referred to as "receptor potential", (ii) the interspike-interval function (Awiszus 1988a) and (iii) the phase lag function which is introduced in this paper. The behaviour of these three functions for constant and dynamically varying input is studied at the Hodgkin-Huxley model (Hodgkin and Huxley 1952) because for this model neuron it is possible to compare the input current estimates obtained from the output functions with the true input current. It was found that for constant and for sufficiently slow varying input all three functions allow a valid reconstruction of the input current time course. On the other hand, if the input current changes rapidly all three estimated input current time courses show considerable deviations from the true time course. The largest maximal deviation is shown by the current estimate obtained from the receptor potential whereas the phase lag function yields the smallest input current misjudgement. An experimental example to illustrate the procedure to obtain the phase lag function for a muscle spindle primary afferent is given.
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PMID:Continuous functions for the analysis of sensory transduction. 274 19

1. Intracellular microelectrode recordings from large sensory and motor myelinated axons in spinal roots of Rana pipiens were used to study the effects of dendrotoxin (DTX), a specific blocker of a fast activating potassium current (GKf1). 2. Dendrotoxin reduced the ability of myelinated sensory and motor axons to accommodate to a constant stimulus. A depolarizing current step, which normally evoked only one action potential, after dendrotoxin treatment (200-500 nM) produced a train of action potentials. These spike trains lasted 29 +/- 2.8 (SE) ms on average in sensory fibers (n = 18) and 40.2 +/- 4.5 ms in motor fibers (n = 9). 3. After dendrotoxin treatment, in addition to a reduction in the ability to accommodate to a constant stimulus, a slowing in the rate of action potential generation was evident (spike frequency adaptation). 4. Dendrotoxin had no effect on the rising phase of conducted action potentials evoked by peripheral stimulation. Together with a lack of effect on the absolute refractory period, these results indicate that dendrotoxin does not affect sodium channel activity. 5. The steady-state voltage/current relationship was unchanged in response to hyperpolarizing current pulses; however, there was a significant increase in cord resistance in response to depolarizing current steps, demonstrating that DTX decreases outward rectification. 6. A computer model based on Hodgkin and Huxley equations was developed, which included the three voltage-dependent potassium conductances described by Dubois. The model reproduced major experimental results: removal of the conductance, termed GKf1, reduced the accommodation in the early phase of a continuous stimulus, indicating that this current could be responsible for the early accommodation. The hypothesis that the slow potassium conductance GKs regulates late accommodation and action potential frequency adaptation is also supported by the computer model. 7. In summary, these results suggest that in amphibian myelinated sensory and motor axons, the activity of potassium conductances can account for accommodation and adaptation without involvement of sodium conductance activity.
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PMID:Dendrotoxin blocks accommodation in frog myelinated axons. 278 43

1. As a preliminary to chemical studies an estimate has been made of the equilibrium dissociation constant (K) for the interaction of tetrodotoxin (TTX) with the non-myelinated fibres of the rabbit desheathed vagus nerve.2. TTX causes a parallel shift to the right of the curves obtained when either the height or the conduction velocity of the compound action potential are plotted against the logarithm of the external sodium concentration.3. A model has been formulated based on the independence principle and the Hodgkin-Huxley theory, and the experimental results shown to be consistent with it. On this basis, and on the assumptions that one TTX molecule blocks one sodium channel, and that binding is Langmuir, K was estimated to be about 3-5 nM at about 20 degrees C. Other simple non-Langmuir models gave essentially similar low values for K.4. An alternative method of computing K that makes rather different assumptions gives a similar low value.5. Despite the low value for K, a TTX concentration of at least 100 nM is needed to block conduction completely and this seems to be related to the fact that conduction is not completely blocked until the external sodium concentration falls below 7% of its value in normal Locke.6. The minimum sodium concentration needed to support conduction increased with temperature.
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PMID:The interaction at equilibrium between tetrodotoxin and mammalian non-myelinated nerve fibres. 501 60

We have studied the effect of N-bromoacetamide (NBA) on the behavior of single sodium channel currents in excised patches of rat myotube membrane at 10 degree C. Inward sodium currents were activated by voltage steps from holding potentials of about -100 mV to test potentials of -40 mV. The cytoplasmic-face solution was isotonic CsF. Application of NBA or pronase to the cytoplasmic face of the membrane irreversibly removed sodium channel inactivation, as determined by averaged single-channel records. Teh lifetime of the open channel at -40 mV was increased about 10-fold by NBA treatment without affecting the amplitude of single-channel currents. A binomial analysis was used both before and after treatment to determine the number of channels within the excised patch. NBA was shown to have little effect on activation kinetics, as determined by an examination of both the rising phase of averaged currents and measurements f the delay between the start of the pulse and the first channel opening. Our data support a kinetic model of sodium channel activation in which the rate constant leading back from the open state to the last closed state is slower than expected from a strict Hodgkin-Huxley model. The data also suggest that the normal open-channel lifetime is primarily determined by the inactivation process in the voltage range we have examined.
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PMID:Effect of N-bromoacetamide on single sodium channel currents in excised membrane patches. 628 57

Inactivation of sodium conduction across the membrane of rat single heart cells was studied by the patch-voltage-clamp method. The development of sodium channel inactivation was found to be double-exponential. Dependence of both time constants on the membrane potential was measured. The time course of the recovery of the sodium conduction from inactivation was sigmoidal in shape with marked retardation at the beginning. The data obtained are not covered by the Hodgkin-Huxley formalismus.
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PMID:[Inactivation of fast sodium current across the membrane of isolated cardiocytes]. 629 9


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