scholarly journals Voltage modulates halothane-triggered Ca2+ release in malignant hyperthermia-susceptible muscle

2017 ◽  
Vol 150 (1) ◽  
pp. 111-125 ◽  
Author(s):  
Alberto Zullo ◽  
Martin Textor ◽  
Philipp Elischer ◽  
Stefan Mall ◽  
Andreas Alt ◽  
...  
Keyword(s):  
Membrane Potential ◽  
Malignant Hyperthermia ◽  
Time Course ◽  
Voltage Dependence ◽  
Muscle Fibers ◽  
Volatile Anesthetic ◽  
Resting Membrane Potential ◽  
Drug Induced ◽  
Anesthetic Drugs ◽  
Malignant Hyperthermia Susceptible

Malignant hyperthermia (MH) is a fatal hypermetabolic state that may occur during general anesthesia in susceptible individuals. It is often caused by mutations in the ryanodine receptor RyR1 that favor drug-induced release of Ca2+ from the sarcoplasmic reticulum. Here, knowing that membrane depolarization triggers Ca2+ release in normal muscle function, we study the cross-influence of membrane potential and anesthetic drugs on Ca2+ release. We used short single muscle fibers of knock-in mice heterozygous for the RyR1 mutation Y524S combined with microfluorimetry to measure intracellular Ca2+ signals. Halothane, a volatile anesthetic used in contracture testing for MH susceptibility, was equilibrated with the solution superfusing the cells by means of a vaporizer system. In the range 0.2 to 3%, the drug causes significantly larger elevations of free myoplasmic [Ca2+] in mutant (YS) compared with wild-type (WT) fibers. Action potential–induced Ca2+ signals exhibit a slowing of their time course of relaxation that can be attributed to a component of delayed Ca2+ release turnoff. In further experiments, we applied halothane to single fibers that were voltage-clamped using two intracellular microelectrodes and studied the effect of small (10-mV) deviations from the holding potential (−80 mV). Untreated WT fibers show essentially no changes in [Ca2+], whereas the Ca2+ level of YS fibers increases and decreases on depolarization and hyperpolarization, respectively. The drug causes a significant enhancement of this response. Depolarizing pulses reveal a substantial negative shift in the voltage dependence of activation of Ca2+ release. This behavior likely results from the allosteric coupling between RyR1 and its transverse tubular voltage sensor. We conclude that the binding of halothane to RyR1 alters the voltage dependence of Ca2+ release in MH-susceptible muscle fibers such that the resting membrane potential becomes a decisive factor for the efficiency of the drug to trigger Ca2+ release.

Hypersensitivity of Malignant Hyperthermia–susceptible Swine Skeletal Muscle to Caffeine Is Mediated by High Resting Myoplasmic [Ca2+]

2000 ◽  
Vol 92 (6) ◽  
pp. 1799-1806 ◽  
Author(s):  
Jose R. López ◽  
Jaime Contreras ◽  
Nancy Linares ◽  
Paul D. Allen
Keyword(s):  
Skeletal Muscle ◽  
Malignant Hyperthermia ◽  
Muscle Fibers ◽  
Resting Membrane Potential ◽  
Free Calcium ◽  
Release Channel ◽  
Malignant Hyperthermia Susceptible ◽  
Before And After ◽  
Increased Sensitivity ◽  
Free Calcium Concentration

Background Malignant hyperthermia (MH) is an inherited pharmacogenetic syndrome that is triggered by halogenated anesthetics and/or depolarizing muscle relaxants. MH-susceptible (MHS) skeletal muscle has been shown to be more sensitive to caffeine-induced contracture than muscle from nonsusceptible (MHN) subjects and is the basis for the most commonly used clinical diagnostic test to determine MH susceptibility. Methods We studied the effects of caffeine on myoplasmic free calcium concentration ([Ca2+]i) in MHN and MHS swine muscle fibers by means of Ca2+-selective microelectrodes before and after K+-induced partial depolarization. Results [Ca2+]i in untreated MHN fibers was 123 +/- 8 nm versus 342 +/- 33 nm in MHS fibers. Caffeine (2 mm) caused an increase in [Ca2+]i in both groups (296 +/- 41 nm MHN vs. 1,159 +/- 235 nm MHS) with no change in resting membrane potential. When either MHN or MHS, muscle fibers were incubated in 10 mm K+ [Ca2+]i transiently increased to 272 +/- 22 nm in MHN and 967 +/- 38 nm in MHS for 6-8 min. Exposure of MHN fibers to 2 mm caffeine while resting [Ca2+]i was elevated induced an increment in [Ca2+]i to 940 +/- 37 nm. After 6-8 min of exposure to 10 mm K+, [Ca2+]i returned to control levels in all fibers, and the effect of 2 mm caffeine on resting [Ca2+]i returned to control, despite continued partial membrane depolarization. Conclusions These results suggest that the increased "sensitivity" to caffeine of MHS swine muscle fibers is a nonspecific response related, at least in part, to the high resting [Ca2+]i and not an increased caffeine sensitivity of the sarcoplasmic reticulum Ca2+ release channel per se.

scholarly journals The hyperpolarization-activated current shifts the dynamic range of a voltage-dependent electrical synapse

2021 ◽  
Author(s):  
Wolfgang Stein ◽  
Margaret DeMaegd ◽  
Lena Yolanda Braun ◽  
Andrés G Vidal-Gadea ◽  
Allison L Harris ◽  
...  
Keyword(s):  
Membrane Potential ◽  
Motor Neuron ◽  
Axon Terminal ◽  
Voltage Dependence ◽  
Dynamic Range ◽  
Complex Dynamics ◽  
Ionic Current ◽  
Electrical Synapse ◽  
Resting Membrane Potential ◽  
Voltage Dependent

Like their chemical counterparts, electrical synapses show complex dynamics such as rectification and voltage dependence that interact with other electrical processes in neurons. The consequences arising from these interactions for the electrical behavior of the synapse, and the dynamics they create, remain largely unexplored. Using a voltage-dependent electrical synapse between a descending modulatory projection neuron (MCN1) and a motor neuron (LG) in the crustacean stomatogastric ganglion, we find that the influence of the hyperpolarization-activated inward current (Ih) is critical to the function of the electrical synapse. When we blocked Ih with CsCl, the voltage dependence of the electrical synapse shifted by 18.7 mV to more hyperpolarized voltages, placing the dynamic range of the electrical synapse outside of the range of voltages used by the LG motor neuron (-60.2 mV to -44.9 mV). With dual electrode current- and voltage-clamp recordings, we demonstrate that this voltage shift is due to a sustained effect of Ih on the presynaptic MCN1 axon terminal membrane potential. Ih-induced depolarization of the axon terminal membrane potential increased the electrical postsynaptic potentials and currents. With Ih present, the axon terminal resting membrane potential depolarized, shifting the dynamic range of the electrical synapse towards the functional range of the motor neuron. We thus demonstrate that the function of an electrical synapse is critically influenced by a voltage-dependent ionic current (Ih).

Conductance changes underlying a late synaptic hyperpolarization in hippocampal CA3 neurons

1987 ◽  
Vol 58 (1) ◽  
pp. 160-179 ◽  
Author(s):  
J. J. Hablitz ◽  
R. H. Thalmann
Keyword(s):  
Membrane Potential ◽  
Voltage Clamp ◽  
Time Course ◽  
Membrane Potentials ◽  
Resting Membrane Potential ◽  
Extracellular Potassium ◽  
Voltage Sensitivity ◽  
Base Line ◽  
Membrane Hyperpolarization ◽  
Ca3 Neurons

1. Single-electrode current- and voltage-clamp techniques were employed to study properties of the conductance underlying an orthodromically evoked late synaptic hyperpolarization or late inhibitory postsynaptic potential (IPSP) in CA3 pyramidal neurons in the rat hippocampal slice preparation. 2. Late IPSPs could occur without preceding excitatory postsynaptic potentials at the resting membrane potential and were graded according to the strength of the orthodromic stimulus. The membrane hyperpolarization associated with the late IPSP peaked within 140-200 ms after orthodromic stimulation of mossy fiber afferents. The late IPSP returned to base line with a half-decay time of approximately 200 ms. 3. As determined from constant-amplitude hyperpolarizing-current pulses, the membrane conductance increase during the late IPSP, and the time course of its decay, were similar whether measurements were made near the resting membrane potential or when the cell was hyperpolarized by approximately 35 mV. 4. When 1 mM cesium was added to the extracellular medium to reduce inward rectification, late IPSPs could be examined over a range of membrane potentials from -60 to -140 mV. For any given neuron, the late IPSP amplitude-membrane potential relationship was linear over the same range of membrane potentials for which the slope input resistance was constant. The late IPSP reversed symmetrically near -95 mV. 5. Intracellular injection of ethyleneglycol-bis-(beta-aminoethylether)-N,N'-tetraacetic acid or extracellular application of forskolin, procedures known to reduce or block certain calcium-dependent potassium conductances in CA3 neurons, had no significant effect on the late IPSP. 6. Single-electrode voltage-clamp techniques were used to analyze the time course and voltage sensitivity of the current underlying the late IPSP. This current [the late inhibitory postsynaptic current (IPSC)] began as early as 25 ms after orthodromic stimulation and reached a peak 120-150 ms following stimulation. 7. The late IPSC decayed with a single exponential time course (tau = 185 ms). 8. A clear reversal of the late IPSC at approximately -99 mV was observed in a physiological concentration of extracellular potassium (3.5 mM).(ABSTRACT TRUNCATED AT 400 WORDS)

Gating currents in the node of Ranvier: voltage and time dependence

1975 ◽  
Vol 270 (908) ◽  
pp. 483-492 ◽  
Keyword(s):  
Membrane Potential ◽  
Time Constant ◽  
Time Course ◽  
Voltage Dependence ◽  
Sudden Change ◽  
Node Of Ranvier ◽  
Ionic Currents ◽  
Gating Currents ◽  
Myelinated Nerve ◽  
Sodium Conductance

Like the axolemma of the giant nerve fibre of the squid, the nodal membrane of frog myelinated nerve fibres after blocking transmembrane ionic currents exhibits asymmetrical displacement currents during and after hyperpolarizing and depolarizing voltage clamp pulses of equal size. The steady-state distribution of charges as a function of membrane potential is consistent with Boltzmann’s law (midpoint potential —33.7 mV; saturation value 17200 charges/(μm 2 ). The time course of the asymmetry current and the voltage dependence of its time constant are consistent with the notion that due to a sudden change in membrane potential the charges undergo a first order transition between two configurations. Size and voltage dependence of the time constant are similar to those of the activation of the sodium conductance assuming m 2 h kinetics, The results suggest the presence of ten times more sodium channels (5000/μm2) in the node of Ranvier than in the squid giant axon with similar sodium conductance per channel (2-3 pS),

scholarly journals Dexmedetomidine as Part of Balanced Anesthesia Care in Children With Malignant Hyperthermia Risk and Egg Allergy

2011 ◽  
Vol 16 (2) ◽  
pp. 113-117
Author(s):  
Elisabeth Dewhirst ◽  
Aymen Naguib ◽  
Joseph D. Tobias
Keyword(s):  
Malignant Hyperthermia ◽  
Volatile Anesthetic ◽  
Anesthesia Care ◽  
Egg Allergy ◽  
Intravenous Anesthesia ◽  
Volatile Anesthetic Agent ◽  
Malignant Hyperthermia Susceptible ◽  
Balanced Anesthesia ◽  
Personal Histories ◽  
Anesthesia Technique

ABSTRACT Malignant hyperthermia is an acute hypermetabolic crisis triggered in susceptible patients by the administration of succinylcholine or a volatile anesthetic agent. When anesthesia care is provided to malignant hyperthermia-susceptible patients, a total intravenous anesthesia technique with propofol is frequently chosen. However, coexisting allergies to egg and soybeans may contraindicate the use of propofol. We present our experience with the use of dexmedetomidine as part of the anesthesia regimen in 3 patients with family histories of malignant hyperthermia and personal histories of egg or soybean allergies. In 2 patients, dexmedetomidine was used as part of a general anesthesia regimen and for sedation during spinal anesthesia in the third patient. Previous reports of the use of dexmedetomidine in patients susceptible to malignant hyperthermia are reviewed, and its benefits in such patients are discussed.

Physiological properties of primate lumbar motoneurons

1992 ◽  
Vol 68 (4) ◽  
pp. 1121-1132 ◽  
Author(s):  
J. S. Carp
Keyword(s):  
Membrane Potential ◽  
Action Potential ◽  
Cell Size ◽  
Current Pulse ◽  
Time Course ◽  
Triceps Surae ◽  
Resting Membrane Potential ◽  
Action Potential Amplitude ◽  
Lateral Gastrocnemius ◽  
Potential Amplitude

1. Intracellular recordings were obtained from 149 motoneurons innervating triceps surae (n = 109) and more distal muscles (n = 40) in 14 pentobarbital-anesthetized monkeys (Macaca nemestrina). The variables evaluated were resting membrane potential, action potential amplitude, conduction velocity (CV), input resistance (RN), membrane time constant (tau m), electrotonic length (L), whole-cell capacitance (Ctot), long current pulse threshold (rheobase), short current pulse threshold (Ishort), afterhyperpolarization (AHP) maximum amplitude (AHPmax), AHP duration (AHPdur), time to half maximum AHP amplitude (AHP t1/2), depolarization from resting potential to elicit action potential (Vdep), and threshold voltage for action potential discharge (Vthr). 2. Mean values +/- SD for the entire sample of motoneurons are as follows: resting membrane potential -67 +/- 6 mV; action potential amplitude 75 +/- 7 mV; CV 71 +/- 6 m/s; RN 1.0 +/- 0.5 M omega; tau m 4.4 +/- 1.5 ms; L 1.4 +/- 0.2 lambda; Ctot 7.1 +/- 1.8 nF; rheobase 13 +/- 7 nA; Ishort 29 +/- 14 nA; AHPmax 3.5 +/- 1.3 mV; AHPdur 77 +/- 26 ms; AHP t 1/2 21 +/- 7 ms; Vdep 11 +/- 4 mV; and Vthr -56 +/- 5 mV. CV is lower in soleus than in either medial or lateral gastrocnemius motoneurons, and RN is lower and tau m is longer in soleus than in lateral gastrocnemius motoneurons. 3. RN is higher in motoneurons with longer tau m and slower CV. A linear relationship exists between log(CV) and log(1/RN) with a slope of 1.8-2.2 (depending on the action potential amplitude acceptance criteria used), suggesting that membrane resistivity (Rm) does not vary systematically with cell size. 4. Rheobase is higher in motoneurons with lower RN, longer tau m, shorter AHP time course, and higher CV. Ishort and normalized rheobase (i.e., rheobase/Ctot) vary similarly with these motoneuron properties, except that Ishort is independent of tau m and normalized rheobase is independent of CV. 5. Vthr tends to be more depolarized in motoneurons with large Ctot, but the relationship is sufficiently weak so that any systematic variation in Vthr according to cell size probably contributes only minimally to recruitment order. Vthr does not vary systematically with CV, AHP time course, RN, or tau m. 6. Quantitative differences between macaque and cat triceps surae motoneurons are apparent in CV, which is slower in macaque than in cat, and to a lesser extent in tau m and RN, which are lower in macaque than in cat.(ABSTRACT TRUNCATED AT 400 WORDS)

scholarly journals Preparation of Modern Anesthesia Workstations for Malignant Hyperthermia–susceptible Patients

2011 ◽  
Vol 114 (1) ◽  
pp. 205-212 ◽  
Author(s):  
Tae W. Kim ◽  
Michael E. Nemergut ◽  
David S. Warner
Keyword(s):  
Malignant Hyperthermia ◽  
Metabolic Response ◽  
Genetic Disorder ◽  
Volatile Anesthetic ◽  
The United States ◽  
Complex Nature ◽  
Minimum Concentration ◽  
Malignant Hyperthermia Susceptible ◽  
Anesthesia Machines ◽  
Anesthetic Gases

Patients with malignant hyperthermia experience an exaggerated metabolic response when exposed to volatile anesthetic gases and succinylcholine. The minimum concentration of anesthetic gas needed to trigger a malignant hyperthermia crisis in humans is unknown and may remain so because of the inherent risks associated with studying the complex nature of this rare and lethal genetic disorder. The Malignant Hyperthermia Association of the United States provides specific instructions on purging anesthesia machines of volatile agents to reduce the risk of exposure. However, these recommendations were developed from studies of older generation machines. Modern anesthesia workstations are more complex and contain more gas absorbing materials. A review of the literature found the current guidelines inadequate to prepare newer generation workstations, which require more time for purging anesthetic gases, autoclaving or replacement of parts, and modifications to the gas delivery system. Protocols must be developed to prepare newer generation anesthesia machines.

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