The C. elegans heterochronic gene pathway consists of a cascade of regulatory genes that are temporally controlled to specify the timing of developmental events1. Mutations in heterochronic genes cause temporal transformations in cell fates in which stage-specific events are omitted or reiterated2. Here we show that let-7 is a heterochronic switch gene. Loss of let-7 gene activity causes reiteration of larval cell fates during the adult stage, whereas increased let-7 gene dosage causes precocious expression of adult fates during larval stages. let-7 encodes a temporally regulated 21-nucleotide RNA that is complementary to elements in the 3′ untranslated regions of the heterochronic genes lin-14, lin-28, lin-41, lin-42 and daf-12, indicating that expression of these genes may be directly controlled by let-7. A reporter gene bearing the lin-41 3′ untranslated region is temporally regulated in a let-7-dependent manner. A second regulatory RNA, lin-4, negatively regulates lin-14 and lin-28 through RNA–RNA interactions with their 3′ untranslated regions3,4. We propose that the sequential stage-specific expression of the lin-4 and let-7 regulatory RNAs triggers transitions in the complement of heterochronic regulatory proteins to coordinate developmental timing.

The 21-nucleotide let-7 RNA regulates developmental timing in Caenorhabditis elegans

Voltage oscillations in the barnacle giant muscle fiber.

1. Inward currents in chromaffin cells were studied with the patch-clamp technique (Hamill, Marty, Neher, Sakmann & Sigworth, 1981). The intracellular solution contained 120 mM-Cs+ and 20 mM-tetraethylammonium (TEA+). Na+ currents were studied after blockade of Ca2+ channels with 1 mM-Co2+ applied externally. Ca2+ currents were recorded after eliminating Na+ currents with tetrodotoxin (TTX). The current recordings were obtained in cell-attached, outside-out and whole-cell recording configurations (Hamill et al. 1981).

2. Single channel measurements gave an elementary current amplitude of 1 pA at -10 mV for Na+ channels. This amplitude increased with hyperpolarization between -10 and -40 mV, but did not vary significantly between -40 and -70 mV.

3. The mean Na+ channel open time was 1 ms at -30 mV. This open time decreased both with depolarization and hyperpolarization. Its value was close to the time constant of inactivation, τh, above -20 mV.

4. Ensemble fluctuation analysis of Na+ currents gave results consistent with those of single channel measurements. Noise power spectra obtained between -35 mV and 0 mV could be fitted with a single Lorentzian. A range of Na+ channel densities of 1·5-10 channels per μm2 was calculated.

5. Cell-attached single Ca2+ channel recordings were obtained in isotonic BaCl2 solution. The single channel amplitude was 0·9 pA at -5 mV, and it became smaller for positive potential values.

6. At -5 mV, single Ba2+ currents appeared as bursts of 1·9 ms mean duration containing on the average 0·6 short gaps. The burst duration was larger at positive potentials.

7. Ensemble fluctuation analysis of Ca2+ channels was performed on whole-cell recordings in external solutions containing isotonic BaCl2 or external Ca2+ (Cao) concentrations of 1 and 5 mM. The unit amplitude calculated in the former case was similar to that obtained in single channel measurements.

8. Noise power spectra of Ca2+ or Ba2+ currents could be fitted by the sum of two, but not one, Lorentzian components.

9. Tail currents could be fitted by the sum of two exponential components. The corresponding time constants had values close to those obtained with noise analysis.

10. The rising phase of Ca2+ and Ba2+ currents was sigmoid. It could be fitted by the sum of three exponentials. The time constant of the largest amplitude component, τ1, was similar to the time constants of the slow component observed in noise and tail experiments. This time constant also corresponded to the burst duration obtained in single channel measurements.

11. The value of τ1 was larger in 5 mM-Cao and in isotonic Ba2+ than in 5 mM-Bao. Thus, the kinetic properties of Ca2+ channels depend on the nature and concentration of the permeating ion.

12. A simple kinetic scheme is proposed to model the activation pathway of Ca2+ channels.

13. Currents in 1 mM-Cao and 5 mM-Cao showed clear reversals around +53 mV and +64 mV respectively. The outward currents observed above these potentials are most probably due to Cs+ ions flowing through Ca2+ channels.

14. The instantaneous current—voltage relation was obtained from tail current data in the range -70 to +100 mV in 5 mM-Cao. The resulting curve displayed an inflexion point around the reversal potential.

15. Very little inactivation of Ca2+ currents was observed. However, a slow current decline was observed in some cells above +10 mV.

16. Conditioning prepulses to positive potentials had potentiating or depressing effects on Ca2+ currents depending on whether the test pulse lay below or above the maximal current potential. The potentiating effect may be linked to the slowest component of the current rise observed below +10 mV. The depressing effect may be related to the slow decline obtained above +10 mV.

17. Analysis of ensemble variance and of tail current amplitudes suggested that the opening probability of Ca2+ channels was at least 0·9 above +40 mV.

18. A slow rundown of Ca2+ currents was observed in whole-cell recordings. The speed of the rundown was dependent on intracellular Ca2+ concentration. The rundown was apparently due to a progressive elimination of the channels available for activation.

19. The density of Ca2+ channels (before rundown) was estimated at 5-15/μm2.

20. In cell-attached experiments, inward current channels were often seen to follow action potentials. These events did not appear to be the usual Na+ and Ca2+ currents. They were probably due to cation influx of either Na+ or Ba2+, depending on the pipette solution, through Ca2+-dependent channels. Voltage-independent single channel activity observed in whole-cell and outside-out recordings may be due to the same channels.

https://physoc.onlinelibrary.wiley.com/doi/pdf/10.1113/jphysiol.1982.sp014394

Sodium and calcium channels in bovine chromaffin cells

In voltage-dependent Na, K, or Ca channels, the probability of opening is modified by the membrane potential. This is achieved through a voltage sensor that detects the voltage and transfers its energy to the pore to control its gate. We present here the theoretical basis of the energy coupling between the electric field and the voltage, which allows the interpretation of the gating charge that moves in one channel. Movement of the gating charge constitutes the gating current. The properties are described, along with macroscopic data and gating current noise analysis, in relation to the operation of the voltage sensor and the opening of the channel. Structural details of the voltage sensor operation were resolved initially by locating the residues that make up the voltage sensor using mutagenesis experiments and determining the number of charges per channel. The changes in conformation are then analyzed based on the differential exposure of cysteine or histidine-substituted residues. Site-directed fluorescence labeling is then analyzed as another powerful indicator of conformational changes that allows time and voltage correlation of local changes seen by the fluorophores with the global change seen by the electrophysiology of gating currents and ionic currents. Finally, we describe the novel results on lanthanide-based resonance energy transfer that show small distance changes between residues in the channel molecule. All of the electrophysiological and the structural information are finally summarized in a physical model of a voltage-dependent channel in which a change in membrane potential causes rotation of the S4 segment that changes the exposure of the basic residues from an internally connected aqueous crevice at hyperpolarized potentials to an externally connected aqueous crevice at depolarized potentials.

The Voltage Sensor in Voltage-Dependent Ion Channels

Obligatory, coupled cotransport of Na+, K+, and Cl− by cell membranes has been reported in nearly every animal cell type. This review examines the current status of our knowledge about this ion tra...

Sodium-Potassium-Chloride Cotransport

Gating currents were measured by subtracting the linear component of the capacitative current recorded at very positive or very negative potentials. When the membrane is depolarized for a few minutes, repolarized to the usual holding potential (HP) of --70 mV for 1 ms, and then pulsed to 0 mV, the charge transferred in 2--4 ms is approximately 50% of that which was transferred during the same pulse holding at --70 mV. This charge decrease, called slow inactivation of the gating current, was found to be consistent with a shift of the charge vs. potential (Q-V) curve to more hyperpolarized potentials. When the HP is 0 mV, the total charge available to move is the same as the total charge available when the HP is --70 mV. The time constants of the fast component of the ON gating current are smaller at depolarized holding potentials than at --70 mV. When the HP is --70 mV and a prepulse of 50 ms duration is given to 0 mV, the Q-V curve is also shifted to more hyperpolarized potentials (charge immobilization), but the effect is not as pronounced as the one obtained by holding at 0 mV. When the HP is 0 mV, a prepulse to --70 mV for 50 ms partially shifts back the Q-V curve, indicating that fast inactivation of the gating charge may be recovered in the presence of slow inactivation. A physical model consisting of a gating particle that interacts with a fast inactivating particle, and a slow inactivating particle, reproduces most of the experimental results.

https://rupress.org/jgp/article-pdf/79/1/21/1248108/21.pdf

Distribution and kinetics of membrane dielectric polarization. 1. Long-term inactivation of gating currents.

Voltage-clamped squid giant axons, perfused internally and externally with solutions containing 10(-5) M dipicrylamine (DpA-), show very large polarization currents (greater than or equal to 1 mA/cm2) in response to voltage steps. The induced polarization currents are shown in the frequency domain as a very large voltage-and frequency-dependent capacitance that can be fit by single Debye-type relaxations. In the time domain, the decay phase of the induced currents can be fit by single exponentials. The induced polarization currents can also be observed in the presence of large sodium and potassium currents. The presence of the DpA- molecules does not affect the resting potential of the axons, but the action potentials appear graded, with a much-reduced rate of rise. The data in the time domain as well as the frequency domain can be explained by a single-barrier model where the DpA- molecules translocate for an equivalent fraction of the electric field of 0.63, and the forward and backward rate constants are equal at -15 mV. When the induced polarization currents described here are added to the total ionic current expression given by Hodgkin and Huxley (1952), numerical solutions of the membrane action potential reproduce qualitatively our experimental data. Numerical solutions of the propagated action potential predict that large changes in the speed of conduction are possible when polarization currents are induced in the axonal membrane. We speculate that either naturally occurring substances or drugs could alter the cable properties of cells in a similar manner.

https://rupress.org/jgp/article-pdf/82/3/331/1248439/331.pdf

Induced capacitance in the squid giant axon. Lipophilic ion displacement currents.

Leakage current rectification in the squid giant axon.

Modification of permeability of frog perineurium to [14C]-sucrose by stretch and hypertonicity

Ionic permeabilities of the frog perineurium

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