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)

A model for the gramicidin A channel is proposed which extends existing models by adding a specific cationic binding site at each entrance to the channel. The binding of ions to these outer channel sites is assumed to shift the energy levels of the inner sites and barriers and thereby alter the channel conductance. The resulting properties are analyzed theoretically for the simplest case of two inner sites and a single energy barrier. This for-site model (two outer and two inner) predicts that the membrane potential at zero current (Uo) should be a Goldman-Hodgkin-Katz equation with concentration-dependent permeability ratios. The coefficients of the concentration-dependent terms are shown to be related to the peak energy shifts of the barrier and to the binding constants of the outer sites. The thory also predicts the channel conductance in symmetrical solutions to exhibit three limiting behaviors, from which the properties of the outer and inner sites can be characterized. In two-cation symmetrical mixtures the conductance as a function of mole fraction is shown to have a minimum, and the related phenomenon of inhibition and block exerted by one ion on the other is explained explicitly by the theory. These various phenomena, having ion interactions in a multiply occupied channel as a common physical basis, are all related (by the theory) through a set of measurable parameters describing the properties of the system.
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PMID:Ionic selectivity, saturation and block in gramicidin A channels: I. Theory for the electrical properties of ion selective channels having two pairs of binding sites and multiple conductance states. 6 17

Intracellular perfusion of giant axons from Loligo forbesi with a crude protein extract of Pronase dissolved in a KF solution suppresses the process of fast inactivation of the Na conductance (the h-process in the Hodgkin-Huxley terminology). 2. The results with protease inhibitors indicate that the most substrate specific endopeptidase present in pronase, alkaline proteinase b, destroys the h-process. 3. After destruction of the inactivation the conductance rise upon depolarization followed cube law kinetics. Values of the time constant taum before and after destruction of the h-process were very similar. 4. After destruction of the inactivation process the following properties were tested: cation selectivity, instantaneous conductance and internal receptor sites for tetrodotoxin (TTX) and tetraethylammonium (TEA). No detectable changes in selectivity or instantaneous conductance were observed. No internal receptors for TTX affecting the Na conductance were found but a TEA receptor is exposed by the protein hydrolysis. 5. TEA derivatives (triethylammonium, TEA-, with an aliphatic chain, Cn) induce a partial block of the steady-state sodium current and induce a time-dependent blockage of the conductance. 6. The first effect of TEA-Cn could be described in terms of a unimolecular reaction with the following equilibrium constants: 50, 2-5, 1-0, 0-4 and 0-025 mM for TEA-C2, TEA-C4, TEA-C5, TEA-C7 and TEA-C9 respectively. 7. From the dependence of the equilibrium dissociation constant on the length of the alkyl chain we estimated the free-energy change in 560 cal/mole of CH2. The gain in free energy per CH2 group transferred from aqueous medium to the interior of a non-polar medium is 1000 cal. 8. Although with the data at hand it is impossible to propose the amino-acid sequence of the site cleaved by alkaline proteinase b, we propose that an important functional component is arginine (or lysine).
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PMID:Destruction of the sodium conductance inactivation by a specific protease in perfused nerve fibres from Loligo. 99 46

1. Giant axons from the squids Dosidicus gigas, Loligo forbesi and Loligo vulgaris were internally perfused with 550 or 275 mM KF plus sucrose and bathed in artificial sea water containing 45Ca, 28Mg or mixtures of 45Ca-28Mg or 45Ca-22Na. Resting influxes and extra influxes during voltage-clamp pulses were measured by collecting and counting the internal perfusate. 2. For Dosidicus axons in 10 mM-CaCl2 the resting influx of calcium was 0-016 +/- 0-007 p-mole/cm2 sec and a linear function of external concentration. For two experiments in 10 and 84-7 mM-CaCl2, 100 nM tetrodotoxin had no effect. Resting calcium influx in 10 mM-CaCl2 was 0-017 +/- 0-013 p-mole/cm2 sec for Loligo axons. 3. With 55 mM-MgCl2 outside the average resting magnesium influx was 0-124 +/- 0-080 p-mole/cm2 sec for Loligo axons. Discarding one aberrant point the value is 0-105 +/- 0-046 which is not significantly different from the resting calcium influx for Dosidicus fibres in 55 mM-CaCl2, given as 0-094 p-mole/cm2 sec by the regression line shown in Fig. 1. In two experiments 150 nM tetrodotoxin had no effect. 4. With 430 mM-NaCl outside 100 nM tetrodotoxin reduced the average resting influx of sodium in Dosidicus axon from 27-7 +/- 4-5 to 25-1 +/- 6-2 p-mole/cm2 sec and for Loligo fibres in 460 mM-NaCl from 50-5 +/- 4 to 20 +/- 8 p-mole/cm2 sec. 5. Using depolarizing pulses of various durations, the extra calcium influx occurred in two phases. The early phase was eliminated by external application of tetrodotoxin. The results of analysis are consistent with, but do not rigorously demonstrate, the conclusion that the tetrodotoxin sensitive calcium entry is flowing through the normal sodium channels (cf. Baker, Hodgkin & Ridgway, 1971). 6. Measurements of extra influxes using 22Na and 45Ca simultaneously indicate that the time courses of tetrodotoxin sensitive calcium and sodium entry are similar but not necessarily identical. It is very doubtful that any significant calcium entry occurs before the sodium or is involved in the activation of the sodium system. 7. These measurements confirm for Loligo, as previously shown for Dosidicus axons, that the magnitude and time course of the sodium entry during a depolarizing pulse deduced from electrical measurements is the same as that measured with 22Na. 8. Using 28Mg, or mixtures of 45Ca and 28Mg, we observed a single phase of magnesium entry which was insensitive to external tetrodotoxin or internal tetraethyl ammonium. The magnitude of the magnesium influx was considerably greater than the calcium extra entry and large enough to have been detected in the experiments of Meves & Vogel (1973) if it represented current. 9. We suggest the possibility that the calcium and magnesium extra influxes, after external treatment with tetrodotoxin, during a depolarizing pulse, do not contribute to the measured current.
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PMID:Simultaneous measurements of magnesium, calcium and sodium influxes in perfused squid giant axons under membrane potential control. 120 93

Tris+/Na+ permeability ratios were measured from shifts in the biionic reversal potentials of the macroscopic ACh-induced currents for 3 wild-type (WT), 1 hybrid, 2 subunit-deficient, and 25 mutant nicotinic receptors expressed in Xenopus oocytes. At two positions near the putative intracellular end of M2, 2' (alpha Thr244, beta Gly255, gamma Thr253, delta Ser258) and -1', point mutations reduced the relative Tris+ permeability of the mouse receptor as much as threefold. Comparable mutations at several other positions had no effects on relative Tris+ permeability. Mutations in delta had a greater effect on relative Tris+ permeability than did comparable mutations in gamma; omission of the mouse delta subunit (delta 0 receptor) or replacement of mouse delta with Xenopus delta dramatically reduced relative Tris+ permeability. The WT mouse muscle receptor (alpha beta gamma delta) had a higher relative permeability to Tris+ than the wild-type Torpedo receptor. Analysis of the data show that (a) changes in the Tris+/Na+ permeability ratio produced by mutations correlate better with the hydrophobicity of the amino acid residues in M2 than with their volume; and (b) the mole-fraction dependence of the reversal potential in mixed Na+/Tris+ solutions is approximately consistent with the Goldman-Hodgkin-Katz voltage equation. The results suggest that the main ion selectivity filter for large monovalent cations in the ACh receptor channel is the region delimited by positions -1' and 2' near the intracellular end of the M2 helix.
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PMID:Tris+/Na+ permeability ratios of nicotinic acetylcholine receptors are reduced by mutations near the intracellular end of the M2 region. 159 78

1. Ionic selectivity and affinity for monovalent cations of channels activated by guanosine 3',5'-cyclic monophosphate (cyclic GMP) were studied in excised inside-out patches of plasma membrane from retinal rods of the tiger salamander. Channels were activated by addition of cyclic GMP to the medium bathing the cytoplasmic side of the membrane. The ionic solution at the cytoplasmic side was rapidly changed using the method of Nunn (1987 a). 2. Permeability ratios were calculated with the Goldman-Hodgkin-Katz potential equation from reversal potential measurements for alkali monovalent cations in bi-ionic conditions. The permeability sequence was: Li+:Na+:K+:Rb+:Cs+ = 1.14:1:0.98:0.84:0.58. 3. The selectivity sequence obtained from macroscopic current measurements in bi-ionic conditions at +100 mV was: Na+:K+:Rb+:Li+:Cs+ = 1:1:0.67:0.36:0.25. 4. The organic cations tetramethylammonium (TMA+), choline and tetraethylammonium (TEA+) were not permeant through the cyclic GMP-activated channels and caused a reduction of the Na+ inward current. At -100 mV the current ratio for inward current was 1:0.75:0.58:0.2 in the presence, at the cytoplasmic side, of 110 mM-Na+, TMA+, choline or TEA+ respectively. 5. The concentration dependence of the macroscopic current and the reversal potential was studied by changing the internal concentration of Na+ or K+ or Li+ from 5 mM to 500 mM. The permeability ratios were nearly constant regardless of the permeant ion concentration. 6. The current as a function of internal ion activity could be described by a Michaelis-Menten relation with a half-saturating activity, Km, at +90 mV equal to 249, 203 and 160 mM for Na+, K+ and Li+ respectively. The ratio of the extrapolated saturating current Imax at +90 mV was 1:0.86:0.26 for Na+, K+ and Li+ respectively. 7. The outward currents and the reversal potentials measured in different mixtures of Na+ and Li+ were monotonic function of the mole fraction. 8. These results can be explained by assuming that, at least in a narrow region, the cyclic GMP-activated channel is a one-ion channel, possibly with other poorly voltage-dependent binding sites in a large inner vestibule.
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PMID:Currents carried by monovalent cations through cyclic GMP-activated channels in excised patches from salamander rods. 169 43

Type l voltage-gated K+ channels in murine lymphocytes were studied under voltage clamp in cell-attached patches and in the whole-cell configuration. The kinetics of activation of whole-cell currents during depolarizing pulses could be fit by a single exponential after an initial delay. Deactivation upon repolarization of both macroscopic and microscopic currents was mono-exponential, except in Rb-Ringer or Cs-Ringer solution in which tail currents often displayed "hooks," wherein the current first increased or remained constant before decaying. In some cells type l currents were contaminated by a small component due to type n K+ channels, which deactivate approximately 10 times slower than type l channels. Both macroscopic and single channel currents could be dissected either kinetically or pharmacologically into these two K+ channel types. The ionic selectivity and conductance of type l channels were studied by varying the internal and external permeant ion. With 160 mM K+ in the cell, the relative permeability calculated from the reversal potential with the Goldman-Hodgkin-Katz equation was K+ (identical to 1.0) greater than Rb+ (0.76) greater than NH4+ = Cs+ (0.12) much greater than Na+ (less than 0.004). Measured 30 mV negative to the reversal potential, the relative conductance sequence was quite different: NH4+ (1.5) greater than K+ (identical to 1.0) greater than Rb+ (0.5) greater than Cs+ (0.06) much greater than Na+, Li+, TMA+ (unmeasurable). Single channel current rectification resembled that of the whole-cell instantaneous I-V relation. Anomalous mole-fraction dependence of the relative permeability PNH4/PK was observed in NH4(+)-K+ mixtures, indicating that the type l K+ channel is a multi-ion pore. Compared with other K+ channels, lymphocyte type l K+ channels are most similar to "g12" channels in myelinated nerve.
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PMID:Selectivity and gating of the type L potassium channel in mouse lymphocytes. 187 88

The effects of fatty acids on the ionic currents of the voltage-clamped squid giant axon were investigated using intracellular and extracellular application of the test substances. Fatty acids mainly suppress the Na current but have little effect on the K current. These effects are completely reversed after washing with control solution. The concentrations required to suppress the peak inward current by 50% and Hill number were determined for each fatty acid. ED50 decreased about 1/3 for each increase of one carbon atom. The standard free energy was -3.05 kJ mole-1 for CH2. The Hill number was 1.58 for 2-decenoic acid. The suppression effect of the fatty acids depends on the number of carbon atoms in the compounds and their chemical structure. Suppression of the Na current was clearly observed when the number of carbon atoms exceeded eight. When fatty acids of the same chain length were compared, 2-decenoic acid had strong inhibitory activity, but sebacic acid had no effect at all on the Na channel. The currents were fitted to equations similar to those proposed by Hodgkin and Huxley (J. Physiol. (London) 117:500-544, 1952) and the changes in the parameters of these equations in the presence of fatty acids were calculated. The curve of the steady-state activation parameter (m infinity) for the Na current against membrane potential and the time constant of activation (tau m) were shifted 20 mV in a depolarizing direction by the application of fatty acids. The time constant for inactivation (tau h) was almost no change by application of the fatty acids.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Effects of fatty acids on membrane currents in the squid giant axon. 357 30

1. The movement of sodium ions across the membrane of the squid giant axon was measured by the use of radioactive tracers. Unidirectional fluxes were measured at rest and when the nerve was stimulated. The difference was considered the extra flux association with nerve impulses.2. The extra influx in intact axons at room temperature was 5.5 p-mole/cm(2). impulse. At 6 degrees C the extra influx was 6.5 p-mole/cm(2). impulse giving a Q(10) of 1/1.2.3. In perfused axons a Q(10) of 1/1.6 was obtained for the extra sodium influx in bracketed experiments on individual axons.4. The Q(10) of the extra sodium efflux associated with nerve impulses was found to be 1/1.2 in intact axons.5. Hodgkin & Huxley had predicted a much larger temperature dependence for the extra fluxes. If this difference between prediction and experiment does not result from some experimental error, then the class of models for the ion fluxes suggested by Hodgkin & Huxley may be inapplicable.
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PMID:The temperature dependence of the movement of sodium ions associated with nerve impulses. 481 26

1. A method for measuring the time course of ionic fluxes during a non-propagated membrane action potential is described; the technique combines intracellular perfusion of the squid giant axon with radioactive tracer methods and with a method for controlling the membrane potential during small time intervals.2. The method is used to determine the temporal course of the sodium extra influx during an action potential.3. The results agree with the time course of the permeability change to sodium ions calculated with the Hodgkin & Huxley equations.4. An average extra sodium influx of 7.13 p-mole/cm(2) per action potential was determined at 12 degrees C and of 5.23 p-mole/cm(2) per action potential at 15 degrees C.
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PMID:Time course of the sodium permeability change during a single membrane action potential. 550 Oct 59

Voltage-clamp experiments using the three micro-electrode method were performed to study the temperature dependence of the calcium current ICa in intact twitch skeletal muscle fibres of the frog. Contraction was blocked by recording in hypertonic sucrose solutions. For depolarizations smaller than 0 mV the decay of the transient, slow, inward current, recorded in the presence of external tetraethylammonium (TEA+) and by replacing Cl- for CH3SO3-, followed a complex time course. For larger depolarizations, after the initial inward current, there was a prominent, slow, outward current which showed two phases: after reaching a peak (time to peak 1.0 sec, peak amplitude 20-50 microA/cm2 at 20 mV) it slowly declined to a steady level in about 2-3 sec at 23 degrees C. The inward current was greatly reduced or abolished by the adding of 2 mM-Cd2+ or by replacing external Ca2+ with Mg2+. The amplitude and time course of slow, outward currents were not obviously modified by replacing Ca2+ with Mg2+, having the two described phases. However, in the presence of Cd2+ the first transient phase of the outward current was not detected and only outward currents slowly increasing to a steady level were observed. Reliable ICa records were obtained by further blocking K+ outward currents by incubating the muscles in a K+-free TEA+- and Cs+-containing solution prior to experiments. Tubular space clamp was improved by recording ICa from small fibres with 20-30 microns radius. The decay phase of ICa under a maintained depolarization in incubated muscles was fitted by a single exponential. The corresponding rate constant determined between 12 and 24 degrees C strongly depended on temperature, as expected for a gating process. The values for the activation energy and the corresponding Q10 (calculated for a 10-20 degrees C transition) were respectively: 17.5 +/- 1.0 kcal/mole and 2.9 +/- 0.2 at 0 mV, and 18.0 +/- 1.5 kcal/mole and 3.0 +/- 0.3 at -20 mV. The activation phase of ICa, analysed following the m alpha h Hodgkin-Huxley kinetic model, showed a similar temperature dependence with a Q10 of 3.0 +/- 0.3. The peak amplitude of ICa and the limiting Ca2+ permeability had a lower Q10 value of about 1.6. For a given temperature the rate constant of decay was independent of ICa peak amplitude in disagreement with a current-dependent process (intratubular Ca2+ depletion or intracellular Ca2+ accumulation) for the decay of ICa. In conclusion, our results favour a gating process (inactivation) as the principal mechanism underlying the decay phase of ICa under a maintained depolarization.
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PMID:Calcium-channel gating in frog skeletal muscle membrane: effect of temperature. 630 47


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