Critical Depolarization Research Articles

On molecular steps that activate a voltage sensitive ion channel at critical depolarization

At high transmembrane electric field, a voltage sensitive ion channel is an insulator; when the field is critically reduced, it becomes a conductor of selected ions. The Channel Activation by Electrostatic Repulsion (CAbER) hypothesis proposes that an ordered polarization field of induced dipoles at the high electric field magnitude of the excitable state is overcome by thermal disorder at a critical depolarization. Increased repulsions between positive charges in the S4 segments cause an allosteric transition in which these segments expand and separate in a chiral proteinquake. The increased space allows the P segments to refold and the ion-semiconducting S5 and S6 segments to relax and expand outward in a breathing mode. Stripped permeant ions enter widened hydrogen bonds in the core helices of these segments. Driven by concentration differences and the electric field, the ions hop along transient pathways across the channel, appearing as fractal, stochastic bursts of single-channel currents. To support order amid thermal fluctuations, an object must be of a minimum size. The critical role of an ion channel's size suggests that the evolution of Metazoa became possible only after its DNA had grown enough to code for proteins larger than the correlation length.

Reduced ventricular excitability causes atrioventricular block and depression of heart rate in fish at critically high temperatures.

At critically high temperature, cardiac output in fish collapses as a result of depression of heart rate (bradycardia). However, the cause of bradycardia remains unresolved. To investigate this, rainbow trout (Oncorhynchus mykiss; acclimated at 12°C) were exposed to acute warming while electrocardiograms were recorded. From 12°C to 25.3°C, electrical excitation between different parts of the heart was coordinated, but above 25.3°C, atrial and ventricular beating rates became partly dissociated because of 2:1 atrioventricular (AV) block. With further warming, atrial rate increased to a peak value of 188±22 beatsmin-1 at 27°C, whereas the ventricle rate peaked at 124±10 beatsmin-1 at 25.3°C and thereafter dropped to 111±15 beatsmin-1 at 27°C. In single ventricular myocytes, warming from 12°C to 25°C attenuated electrical excitability as evidenced by increases in rheobase current and the size of critical depolarization required to trigger action potential. Depression of excitability was caused by temperature-induced decrease in input resistance (sarcolemmal K+ leak via the outward IK1 current) of resting myocytes and decrease in inward charge transfer by the Na+ current (INa) of active myocytes. Collectively, these findings show that at critically high temperatures AV block causes ventricular bradycardia owing to the increased excitation threshold of the ventricle, which is due to changes in the passive (resting ion leak) and active (inward charge movement) electrical properties of ventricular myocytes. The sequence of events from the level of ion channels to cardiac function in vivo provides a mechanistic explanation for the depression of cardiac output in fish at critically high temperature.

Entangled photon-added coherent states

We study the degree of entanglement of arbitrary superpositions of $m,n$ photon-added coherent states (PACS) $|\psi\rangle \propto u |{\alpha},m\rangle |{\beta},n \rangle+ v |{\beta},n\rangle |{\alpha},m\rangle$ using the concurrence, and obtain the general conditions for maximal entanglement. We show that photon addition process can be identified as an entanglement enhancer operation for superpositions of coherent states (SCS). Specifically for the known bipartite positive SCS: $|\psi\rangle \propto |\alpha\rangle_a |-\alpha\rangle_b + |-\alpha\rangle_a |\alpha\rangle_b $ whose entanglement tends to zero for $\alpha \to 0$, can be maximal if al least one photon is added in a subsystem. A full family of maximally entangled PACS is also presented. We also analyzed the decoherence effects in the entangled PACS induced by a simple depolarizing channel. We find that robustness against depolarization is increased by adding photons to the coherent states of the superposition. We obtain the dependence of the critical depolarization $p_{\text{crit}}$ for null entanglement as a function of $m,n, \alpha$ and $\beta $.

Flow- and voltage-dependent blocking effect of ethosuximide on the inward rectifier K⁺ (Kir2.1) channel.

Absence seizures are manifestations of abnormal thalamocortical oscillations characterized by spike-and-wave complexes in EEG. Ethosuximide (ETX) is one of the principal medications against absence seizures. We investigate the effect of ETX on the Kir2.1 channel, a prototypical inward rectifier K(+) channel possibly playing an important role in the setting of neuronal membrane potential. We demonstrate that the outward currents of Kir2.1 channels are significantly inhibited by intracellular ETX. We further show that the movement of neutral molecule ETX in the Kir2.1 channel is accompanied by ∼1.2 K(+), giving rise to the vivid voltage dependence of ETX unbinding rate. Moreover, the apparent affinity (K d ) of ETX in the channels are decreased by single-point mutations involving M183, E224, and S165, and especially by double mutations involving T141/S165, which always also disrupt the flux-coupling feature of ETX block. Molecular dynamics simulation demonstrates narrowing of the pore at ∼D172 by binding of ETX to S165 or T141. ETX block of the Kir2.1 channels may cause a modest but critical depolarization of the relevant neurons, decreasing available T-type Ca(2+) channels and consequently lessening pathological thalamocortical burst discharges.

Myofibroblasts in diseased hearts: New players in cardiac arrhythmias?

Cardiac pathologies leading to the development of organ fibrosis typically are associated with the appearance of interstitial myofibroblasts. This cell type plays a central role in excessive extracellular matrix deposition, thereby contributing to arrhythmogenic slow and discontinuous conduction by causing disorganization of the three-dimensional network of electrically coupled cardiomyocytes. Besides this involvement in structural remodeling, myofibroblasts recently have been discovered in-vitro to promote arrhythmogenesis by direct modification of cardiomyocyte electrophysiology following establishment of heterocellular electrical coupling. In particular, myofibroblasts were found to rescue impulse conduction between disjoined cardiac tissues by acting as passive electrical conduits for excitatory current flow. Although, in principle, such recovery of blocked conduction might be beneficial, propagation across myofibroblast conduits is substantially delayed, thereby promoting arrhythmogenic slow and discontinuous conduction. Second, moderately polarized myofibroblasts were found to induce cell density-dependent depolarization of cardiomyocytes, which causes arrhythmogenic slow conduction due to the reduction of fast inward currents. Finally, critical depolarization of cardiomyocytes by myofibroblasts was discovered to lead to the appearance of ectopic activity in a model of the infarct border zone. These findings obtained in vitro suggest that electrotonic interactions following gap junctional coupling between myofibroblasts and cardiomyocytes in structurally remodeled fibrotic hearts might directly initiate the main mechanisms underlying arrhythmogenesis, that is, abnormal automaticity and abnormal impulse conduction. If, in the future, similar arrhythmogenic mechanisms can be shown to be operational in intact hearts, myofibroblasts might emerge as a novel noncardiomyocyte target for antiarrhythmic therapy.

Endothelin enhances activity of mechanosensitive channels: A mechanism for ET augmentation of the myogenic response

See article by Lee et al. [11] (pages 224–235) in this issue. That stretching smooth muscle can result in contraction has been appreciated for over a hundred years (see [1]), and Bayliss in 1902 [1] demonstrated that an increase in luminal pressure in arteries resulted in passive distension followed by constriction. Neural and hormonal mechanisms were excluded, so mechanisms intrinsic to smooth muscle were invoked to explain this phenomenon, now known as the myogenic response. Reports of stretch-induced activation of depolarization[2] and action potentials [3] in visceral smooth muscle were followed by studies on blood vessels in which increases in luminal pressure were associated with depolarization [4–6] and the initiation of action potentials [4]. Attenuation of the myogenic constriction by Ca2+channel blockers implicated voltage-operated Ca2+channels. But what causes the critical depolarization that activates the Ca2+channels? In a wide range of cell types, including vascular smooth muscle [7], negative pressure applied to patch-clamp electrodes activates various ion channels, particularly poorly selective cation channels. Thus, pressurization of blood vessels stretches their walls which activates stretch-sensitive cation channels, resulting in depolarization that activates voltage-operated Ca2+ channels, and the ensuing influx of Ca2+ initiates constriction. However, additional dimensions add complexity and raise further questions. These are generally centred on the processes that underlie stretch activation of ion channels, the role of the … *Corresponding author. Tel.: +61 3 9905 2520; fax: +61 3 9905 2547. h.coleman{at}med.monash.edu.au

Acute Late Sepsis Attenuates Effects of a Nondepolarizing Neuromuscular Blocker, Rocuronium, by Facilitation of Endplate Potential and Enhancement of Membrane Excitability In Vitro

Sepsis attenuates the muscle-relaxing effects of nondepolarizing neuromuscular blockers. The authors investigated the effects of acute late sepsis on neuromuscular transmission and neuromuscular actions of rocuronium to clarify the mechanisms by which sepsis attenuates the effects of nondepolarizing neuromuscular blockers. Sepsis was induced by cecal ligation and puncture operation. Endplate potentials, acetylcholine potentials, and electrotonic potentials were recorded from the motor endplates of isolated diaphragms from acute late septic and nonseptic rats. (1) Sepsis did not influence the effect of rocuronium to decrease endplate potential amplitude, which was increased by sepsis itself; (2) sepsis facilitated the effect of rocuronium to decrease quantal acetylcholine release, which was increased by sepsis itself; (3) sepsis did not influence the effect of rocuronium to decrease acetylcholine sensitivity, which was decreased by sepsis itself; (4) sepsis decreased critical depolarization, and rocuronium did not influence critical depolarization. These results indicate that acute late sepsis facilitates endplate potentials and enhances excitability of the muscle membrane, indicated by a decrease of critical depolarization. It is thought that these elicit the sepsis-induced attenuation of the muscle-relaxing effects of rocuronium.

The Effects of Changes in Extracellular Calcium Concentrations on the Electrical Properties of Command Neurons after Acquisition of a Defensive Conditioned Reflex in Snails

Studies of the electrical characteristics of the command neurons of a defensive reflex showed that the membrane potential showed no significant changes in response to changes in the calcium concentration in the perfusing solution in either intact or trained snails. Increases in the calcium ion concentration in intact snails were accompanied by increases in the threshold potential, from 14 +/- 0.7 mV at 2.5 mM Ca2+ to 21.8 +/- 0.9 mV at 20 mM Ca2+. The threshold potential in trained snails decreased in response to both increases and decreases in calcium concentrations, from 16.8 +/- 0.6 mV (physiological saline containing 10 mM Ca2+) to 13.3 +/- 0.6 mV at 20 mM Ca2+ and 11.8 +/- 0.8 mV at 2.5 mM Ca2+. The critical depolarization level changed correspondingly: in intact snails, this decreased with increases in calcium concentration, while in trained snails it increased in response to both increases and decreases in the calcium concentration.

Determinants of action potential initiation in isolated rabbit atrial and ventricular myocytes.

Action potential conduction through the atrium and the ventricle of the heart depends on the membrane properties of the atrial and ventricular cells, particularly with respect to the determinants of the initiation of action potentials in each cell type. We have utilized both current- and voltage-clamp techniques on isolated cells to examine biophysical properties of the two cell types at physiological temperature. The resting membrane potential, action potential amplitude, current threshold, voltage threshold, and maximum rate of rise measured from atrial cells (-80 +/- 1 mV, 109 +/- 3 mV, 0.69 +/- 0.05 nA, -59 +/- 1 mV, and 206 +/- 17 V/s, respectively; means +/- SE) differed significantly (P < 0.05) from those values measured from ventricular cells (-82.7 +/- 0.4 mV, 127 +/- 1 mV, 2.45 +/- 0.13 nA, -46 +/- 2 mV, and 395 +/- 21 V/s, respectively). Input impedance, capacitance, time constant, and critical depolarization for activation also were significantly different between atrial (341 +/- 41 M omega, 70 +/- 4 pF, 23.8 +/- 2. 3 ms, and 19 +/- 1 mV, respectively) and ventricular (16.5 +/- 5.4 M omega, 99 +/- 4.3 pF, 1.56 +/- 0.32 ms, and 36 +/- 1 mV, respectively) cells. The major mechanism of these differences is the much greater magnitude of the inward rectifying potassium current in ventricular cells compared with that in atrial cells, with an additional difference of an apparently lower availability of inward Na current in atrial cells. These differences in the two cell types may be important in allowing the atrial cells to be driven successfully by normal regions of automaticity (e.g., the sinoatrial node), whereas ventricular cells would suppress action potential initiation from a region of automaticity (e.g., an ectopic focus).

GABAB autoreceptors regulate the induction of LTP

Understanding the mechanisms involved in long-term potentiation (LTP) should provide insights into the cellular and molecular basis of learning and memory in vertebrates. It has been established that in the CA1 region of the hippocampus the induction of LTP requires the transient activation of the N-methyl-D-aspartate (NMDA) receptor system. During low-frequency transmission, significant activation of this system is prevented by gamma-aminobutyric acid (GABA) mediated synaptic inhibition which hyperpolarizes neurons into a region where NMDA receptor-operated channels are substantially blocked by Mg2+ (refs. 5, 6). But during high-frequency transmission, mechanisms are evoked that provide sufficient depolarization of the postsynaptic membrane to reduce this block and thereby permit the induction of LTP. We now report that this critical depolarization is enabled because during high-frequency transmission GABA depresses its own release by an action on GABAB autoreceptors, which permits sufficient NMDA receptor activation for the induction of LTP. These findings demonstrate a role for GABAB receptors in synaptic plasticity.

Ionic mechanisms of depolarization responses in Helix pomatia neurons to glutamate application

Reversal potentials of transmembrane ionic currents induced by glutamate were determined in various D neurons ofHelix pomatia. Two types of neurons were found with mean reversal potentials of −10.6±1.2 and −40.0±0.6 mV. Neurons of the first group responded under ordinary conditions to glutamate application by a volley of action potentials. Neurons of the second group did not generate action potentials under the same conditions during glutamate application. With an increase in the dose of mediator the amplitude of D responses in these neurons increased only up to a certain limit, without reaching the critical depolarization level of the cell; a fall in the external chloride ion concentration led to a decrease in their reversal potential. The possible ionic mechanisms of glutamate-dependent depolarization responses of these groups of neurons are discussed.

Depolarization of light by critical fluctuations in RbAg4I5

The cubic-to-rhombohedral phase transition in the superionic conductor Rb${\mathrm{Ag}}_{4}$${\mathrm{I}}_{5}$ is characterized by strong birefringence in the rhombohedral phase. Precursive fluctuations in the cubic phase lead to complete depolarization of transmitted light at ${T}_{c}=208$ K. We show that the depolarization increases exponentially as a power of reduced temperature. For the case of a linear relationship between the order parameter and the birefringence, as in Rb${\mathrm{Ag}}_{4}$${\mathrm{I}}_{5}$, the power of temperature in the exponential is the critical exponent $\ensuremath{\gamma}$ which governs the susceptibility-like response function. An experimental value $\ensuremath{\gamma}=1.25\ifmmode\pm\else\textpm\fi{}0.1$ is obtained which agrees well with Ising-like values, and scales with other critical exponents. We believe this to be the first observation of a critical depolarization effect.

Effect of carbon dioxide on the excitable membrane of the single Ranvier node

Addition of 5% CO2 to the atmosphere in the chamber with the specimen caused no significant change in the recorded parameters of the Ranvier node membrane. Increasing the CO2 concentration to 50% (50% CO2+50% O2) caused a significant increase in the resistance and critical depolarization level of the membrane, a decrease in amplitude of the spike and maximal steepness of its rise. Spike generation ceased 2 min after the beginning of exposure to the gas mixture. The action of CO2 was completely reversible. After-potentials of the node were virtually unchanged by the action of CO2 in these concentrations.

On the theory of multiple scattering II. Critical scattering

The systematic theory of multiple scattering which we gave in a previous paper is further elaborated for critical scattering. It is shown that in each order the multiple-scattering intensity near the critical point is in essence a contraction of consecutive uncorrelated single-scattering intensities. The anomaly of the critical depolarization factor is calculated and is found to be in quantitative agreement with recent experimental results. Double scattering corrections to the Ornstein-Zernike plot are discussed.

Effects of pathogenic action of botulinus toxin of spinal motoneurons of various types

Motoneurons of the lumbosacral region of the spinal cord were studied during local botulinus paralysis. The development of paralysis of the poisoned limb was accompanied by lowering of the membrane potential, the amplitude of the antidromic action potentials and of mono- and polysynaptic EPSPs, and the input resistance, and by an increase in the critical depolarization level of the soma membrane of phasic motoneurons in the affected segments of the spinal cord. The excitability of the tonic motoneurons was substantially unchanged in the course of development of local botulism.

Experimental observation of critical depolarization in carbon dioxide

Experimental results are presented for the depolarization factor of light scattered by CO 2 at the critical density. A large critical anomaly has been observed, which is attributed to secondary scattering. A comparison is made with recent theoretical calculations on double scattering.

Calculation of the critical depolarization factor for CO 2

Using a formula for critical double scattering, which we recently obtained, the depolarization factor for CO 2 was calculated. The values are in good agreement with recent experimental results by Trappeniers et al. who found an anomaly close to the critical point.

Hyperthyroid myopathy: Intracellular electrophysiological measurements in biopsied human intercostal muscle

Morphological and electrophysiological studies were performed on intercostal muscle biopsies from 2 thyrotoxic patients. The diseased fibers had numberous areas of subsarcolemmal glycogen accumulations and abnormal membranous projections. Both Type I and II muscle fibers were atrophied. Diseased fibers were substantially depolarized and when artificially hyperpolarized showed earlier inactivation of the sodium conductance as a function of membrane potential, and a critical depolarization potential more depolarized than in normal fibers. When stimulated at 20 pulses/sec, or faster, the diseased fibers could not generate normal action potentials due to membrane depolarization and the appearance of a marked after-hyperpolarization. Muscle weakness associated with hyperthyroidism is attributed to the reduced membrane excitability.

Insect visceral muscle. Responses of the proctodeal muscles to mechanical stretch

The longitudinal muscle fibres of the cockroach proctodeum were found to be sensitive to stretch despite its striated structure. Mechanical and electrical responses triggered by stretch were recorded. Quick stretches applied to the muscle generated electrical responses which caused contractions. Resting membrane potentials decreased during maintained stretch and in proportion to the amount of stretch. A train of rhythmic action potentials was evoked at a critical depolarization level of the resting membrane potential by stretch. Total number and frequency of the responses increased with increasing strength of the maintained stretch. Tension-length curves of active and resting states were measured. Actively developed tension increased up to the state twice the rest length of the muscle. An action potential was generated by directly applied depolarizing current, and stronger depolarization evoked repetitive action potentials. Hyperpolarization blocked the generation of action potentials. It is concluded that in the longitudinal muscle fibres the action potential may be generated by a simple shift of the resting membrane potential towards a critical depolarization level which is achieved not only by PSP's but also by stretch.

The action of general anaesthetic agents on root responses of the frog isolated spinal cord.

1. The action of volatile and barbiturate general anaesthetic agents on synaptic transmission in the frog isolated spinal cord has been studied by recording ventral root synaptic potentials and spike discharges evoked by volleys in a dorsal root and in the lateral column fibres.2. Some observations on the distribution of the lateral column fibres and the characteristics of the dorsal root potentials have been presented.3. Volatile agents depressed and eventually abolished all components of the ventral root responses. Failure of motoneurone discharge was the result of two factors, a decrease in the slope of the synaptic potential and an elevation of the critical depolarization required to trigger propagated impulses.4. Barbiturate compounds, in contrast, readily abolished polysynaptic components of the ventral root responses, but the short latency discharge produced by lateral column stimulation was potentiated, and was accompanied by a lowering of the firing threshold of motoneurones. The mechanism of this potentiation by barbiturate compounds is discussed.5. It is concluded that volatile agents act predominantly on the initial segment and subsynaptic elements of the motoneurone, whereas barbiturate compounds depress the presynaptic or postsynaptic components of interneuronal synapses.