Stochasticity intrinsic to coupled-clock mechanisms underlies beat-to-beat variability of spontaneous action potential firing in sinoatrial node pacemaker cells

Background The capacity of general anesthetics to produce immobility is primarily spinally mediated. Recently, compelling evidence has been provided that the spinal actions of propofol involve gamma-aminobutyric acid type A (GABAA) receptors, whereas the contribution of glycine receptors remains uncertain. The relevant molecular targets of the commonly used volatile anesthetic sevoflurane in the spinal cord are largely unknown, but indirect evidence suggests a mechanism of action distinct from propofol. Methods The effects of sevoflurane and propofol on spontaneous action potential firing were investigated by extracellular voltage recordings from ventral horn interneurons in cultured spinal cord tissue slices obtained from embryonic rats (embryonic days 14-15). Results Propofol and sevoflurane reduced spontaneous action potential firing of neurons. Concentrations causing half-maximal effects (0.11 microm propofol, 0.11 mm sevoflurane) were lower than the median effective concentration immobility (1-1.5 microm propofol, 0.35 mm sevoflurane). At higher concentrations, complete inhibition of action potential activity was observed with sevoflurane but not with propofol. Effects of sevoflurane were mediated predominantly by glycine receptors (45%) and GABAA receptors (38%), whereas propofol acted almost exclusively via GABAA receptors (96%). Conclusions The authors' results suggest that glycine and GABAA receptors are the most important molecular targets mediating depressant effects of sevoflurane in the spinal cord. They provide evidence that sevoflurane causes immobility by a mechanism distinct from the actions of the intravenous anesthetic propofol. The finding that propofol acts exclusively via GABAA receptors can explain its limited capacity to depress spinal neurons in the authors' study.

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Different roles attributed to Cav1 channel subtypes in spontaneous action potential firing and fine tuning of exocytosis in mouse chromaffin cells

Journal of Neurochemistry ◽

10.1111/j.1471-4159.2010.07089.x ◽

2010 ◽

Vol 116 (1) ◽

pp. 105-121 ◽

Cited By ~ 15

Author(s):

Alberto Pérez-Alvarez ◽

Alicia Hernández-Vivanco ◽

Jose Carlos Caba-González ◽

Almudena Albillos

Keyword(s):

Action Potential ◽

Chromaffin Cells ◽

Fine Tuning ◽

Action Potential Firing ◽

Spontaneous Action Potential ◽

Potential Firing ◽

Spontaneous Action

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Effects of volatile anaesthetics on spontaneous action potential firing of cerebellar Purkinje cells in vitro do not follow the Meyer-Overton rule

British Journal of Anaesthesia ◽

10.1093/bja/79.5.617 ◽

1997 ◽

Vol 79 (5) ◽

pp. 617-624 ◽

Cited By ~ 7

Author(s):

B Antkowiak ◽

H Hentschke ◽

K Kirschfeld

Keyword(s):

Action Potential ◽

Purkinje Cells ◽

Volatile Anaesthetics ◽

Action Potential Firing ◽

Spontaneous Action Potential ◽

Potential Firing ◽

Spontaneous Action ◽

Cerebellar Purkinje Cells

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Circadian- and Light-Dependent Regulation of Resting Membrane Potential and Spontaneous Action Potential Firing of Drosophila Circadian Pacemaker Neurons

Journal of Neurophysiology ◽

10.1152/jn.00930.2007 ◽

2008 ◽

Vol 99 (2) ◽

pp. 976-988 ◽

Cited By ~ 121

Author(s):

Vasu Sheeba ◽

Huaiyu Gu ◽

Vijay K. Sharma ◽

Diane K. O'Dowd ◽

Todd C. Holmes

Keyword(s):

Membrane Potential ◽

Action Potential ◽

Activity Patterns ◽

Burst Firing ◽

Resting Membrane Potential ◽

Action Potential Firing ◽

Pacemaker Neurons ◽

Spontaneous Action Potential ◽

Potential Firing ◽

Spontaneous Action

The ventral lateral neurons (LNvs) of adult Drosophila brain express oscillating clock proteins and regulate circadian behavior. Whole cell current-clamp recordings of large LNvs in freshly dissected Drosophila whole brain preparations reveal two spontaneous activity patterns that correlate with two underlying patterns of oscillating membrane potential: tonic and burst firing of sodium-dependent action potentials. Resting membrane potential and spontaneous action potential firing are rapidly and reversibly regulated by acute changes in light intensity. The LNv electrophysiological light response is attenuated, but not abolished, in cry b mutant flies hypomorphic for the cell-autonomous light-sensing protein CRYPTOCHROME. The electrical activity of the large LNv is circadian regulated, as shown by significantly higher resting membrane potential and frequency of spontaneous action potential firing rate and burst firing pattern during circadian subjective day relative to subjective night. The circadian regulation of membrane potential, spontaneous action potential firing frequency, and pattern of Drosophila large LNvs closely resemble mammalian circadian neuron electrical characteristics, suggesting a general evolutionary conservation of both physiological and molecular oscillator mechanisms in pacemaker neurons.

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Cholinergic Modulation of Sevoflurane Potency in Cortical and Spinal Networks In Vitro

Anesthesiology ◽

10.1097/01.anes.0000267598.65120.f2 ◽

2007 ◽

Vol 106 (6) ◽

pp. 1147-1155 ◽

Cited By ~ 17

Author(s):

Christian Grasshoff ◽

Berthold Drexler ◽

Harald Hentschke ◽

Horst Thiermann ◽

Bernd Antkowiak

Keyword(s):

Action Potential ◽

Gabaa Receptor ◽

Gabaa Receptors ◽

Receptor Function ◽

Action Potential Firing ◽

Newborn Mice ◽

Organophosphate Intoxication ◽

Spontaneous Action Potential ◽

Potential Firing ◽

Spontaneous Action

Background Victims of organophosphate intoxication with cholinergic crisis may have need for sedation and anesthesia, but little is known about how anesthetics work in these patients. Recent studies suggest that cholinergic stimulation impairs gamma-aminobutyric acid type A (GABAA) receptor function. Because GABAA receptors are major targets of general anesthetics, the authors investigated interactions between acetylcholine and sevoflurane in spinal and cortical networks. Methods Cultured spinal and cortical tissue slices were obtained from embryonic and newborn mice. Drug effects were assessed by extracellular voltage recordings of spontaneous action potential activity. Results Sevoflurane caused a concentration-dependent decrease in spontaneous action potential firing in spinal (EC50=0.17+/-0.02 mM) and cortical (EC50=0.29+/-0.01 mM) slices. Acetylcholine elevated neuronal excitation in both preparations and diminished the potency of sevoflurane in reducing action potential firing in cortical but not in spinal slices. This brain region-specific decrease in sevoflurane potency was mimicked by the specific GABAA receptor antagonist bicuculline, suggesting that (1) GABAA receptors are major molecular targets for sevoflurane in the cortex but not in the spinal cord and (2) acetylcholine impairs the efficacy of GABAA receptor-mediated inhibition. The latter hypothesis was supported by the finding that acetylcholine reduced the potency of etomidate in depressing cortical and spinal neurons. Conclusions The authors raise the question whether cholinergic overstimulation decreases the efficacy of GABAA receptor function in patients with organophosphate intoxication, thereby compromising anesthetic effects that are mediated predominantly via these receptors such as sedation and hypnosis.

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Effects of Small Concentrations of Volatile Anesthetics on Action Potential Firing of Neocortical Neurons In Vitro

Anesthesiology ◽

10.1097/00000542-199806000-00024 ◽

1998 ◽

Vol 88 (6) ◽

pp. 1592-1605 ◽

Cited By ~ 38

Author(s):

Bernd Antkowiak ◽

Charlotte Helfrich-Forster

Keyword(s):

Action Potential ◽

General Anesthesia ◽

Volatile Anesthetics ◽

Synaptic Inhibition ◽

Action Potential Firing ◽

Gaba A ◽

Neocortical Neurons ◽

Spontaneous Action Potential ◽

Potential Firing ◽

Spontaneous Action

Background Volatile general anesthetics depress neuronal activity in the mammalian central nervous system and enhance inhibitory Cl- currents flowing across the gamma-aminobutyric acid A (GABA(A)) receptor-ion channel complex. The extent to which an increase in GABA(A)-mediated synaptic inhibition contributes to the decrease in neuronal firing must be determined, because many further effects of these agents have been reported on the molecular level. Methods The actions of halothane, isoflurane, and enflurane on the firing patterns of single neurons were investigated by extracellular recordings in organotypic slice cultures derived from the rat neocortex. Results Volatile anesthetics depressed spontaneous action potential firing of neocortical neurons in a concentration-dependent manner. The estimated median effective concentration (EC50) values were about one half the EC50 values for general anesthesia. In the presence of the GABA(A) antagonist bicuculline (20 microM), the effectiveness of halothane, isoflurane, and enflurane in reducing the discharge rates were diminished by 48-65%, indicating that these drugs act via the GABA(A) receptor. Conclusions Together with recent investigations, our results provide evidence that halothane, isoflurane, and enflurane reduced spontaneous action potential firing of neocortical neurons in cultured brain slices mainly by increasing GABA(A)-mediated synaptic inhibition. At concentrations, approximately one half the EC50 for general anesthesia, volatile anesthetics increased overall GABA(A)-mediated synaptic inhibition about twofold, thus decreasing spontaneous action potential firing by half.

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Distinct Effects of Ibrutinib and Acalabrutinib on Mouse Atrial and Sinoatrial Node Electrophysiology and Arrhythmogenesis

Journal of the American Heart Association ◽

10.1161/jaha.121.022369 ◽

2021 ◽

Author(s):

Jari M. Tuomi ◽

Loryn J. Bohne ◽

Tristan W. Dorey ◽

Hailey J. Jansen ◽

Yingjie Liu ◽

...

Keyword(s):

Atrial Fibrillation ◽

Action Potential ◽

Sinoatrial Node ◽

Optical Mapping ◽

Delayed Rectifier ◽

Action Potential Firing ◽

Atrial Electrophysiology ◽

Potential Firing ◽

Beating Rate ◽

Upstroke Velocity

Background Ibrutinib and acalabrutinib are Bruton tyrosine kinase inhibitors used in the treatment of B‐cell lymphoproliferative disorders. Ibrutinib is associated with new‐onset atrial fibrillation. Cases of sinus bradycardia and sinus arrest have also been reported following ibrutinib treatment. Conversely, acalabrutinib is less arrhythmogenic. The basis for these different effects is unclear. Methods and Results The effects of ibrutinib and acalabrutinib on atrial electrophysiology were investigated in anesthetized mice using intracardiac electrophysiology, in isolated atrial preparations using high‐resolution optical mapping, and in isolated atrial and sinoatrial node (SAN) myocytes using patch‐clamping. Acute delivery of acalabrutinib did not affect atrial fibrillation susceptibility or other measures of atrial electrophysiology in mice in vivo. Optical mapping demonstrates that ibrutinib dose‐dependently impaired atrial and SAN conduction and slowed beating rate. Acalabrutinib had no effect on atrial and SAN conduction or beating rate. In isolated atrial myocytes, ibrutinib reduced action potential upstroke velocity and Na + current. In contrast, acalabrutinib had no effects on atrial myocyte upstroke velocity or Na + current. Both drugs increased action potential duration, but these effects were smaller for acalabrutinib compared with ibrutinib and occurred by different mechanisms. In SAN myocytes, ibrutinib impaired spontaneous action potential firing by inhibiting the delayed rectifier K + current, while acalabrutinib had no effects on SAN myocyte action potential firing. Conclusions Ibrutinib and acalabrutinib have distinct effects on atrial electrophysiology and ion channel function that provide insight into the basis for increased atrial fibrillation susceptibility and SAN dysfunction with ibrutinib, but not with acalabrutinib.

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Eclosion hormone provides a link between ecdysis-triggering hormone and crustacean cardioactive peptide in the neuroendocrine cascade that controls ecdysis behavior

Journal of Experimental Biology ◽

10.1242/jeb.202.4.343 ◽

1999 ◽

Vol 202 (4) ◽

pp. 343-352 ◽

Cited By ~ 16

Author(s):

S.C. Gammie ◽

J.W. Truman

Keyword(s):

Action Potential ◽

Motor Program ◽

Action Potential Firing ◽

Nervous Systems ◽

Eclosion Hormone ◽

Bath Application ◽

Crustacean Cardioactive Peptide ◽

Potential Firing ◽

Spontaneous Action ◽

Ecdysis Triggering Hormone

Three insect peptide hormones, eclosion hormone (EH), ecdysis-triggering hormone (ETH) and crustacean cardioactive peptide (CCAP), have been implicated in controlling ecdysis behavior in insects. This study examines the interactions between these three peptides in the regulation of the ecdysis sequence. Using intracellular recordings, we found that ETH is a potent activator of the EH neurons, causing spontaneous action potential firing, broadening of the action potential and an increase in spike peak amplitude. In turn, electrical stimulation of the EH neurons or bath application of EH to desheathed ganglia resulted in the elevation of cyclic GMP (cGMP) levels within the Cell 27/704 group (which contain CCAP). This cGMP production increases the excitability of these neurons, thereby facilitating CCAP release and the generation of the ecdysis motor program. Extracellular recordings from isolated nervous systems show that EH has no effect on nervous systems with an intact sheath. In desheathed preparations, in contrast, EH causes only the ecdysis motor output. The latency from EH application to ecdysis was longer than that after CCAP application, but shorter than that when ETH is applied to a whole central nervous system. These data, along with previously published results, support a model in which ETH causes pre-ecdysis behavior and at higher concentrations stimulates the EH neurones. EH release then facilitates the onset of ecdysis by enhancing the excitability of the CCAP neurons.

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