Computational Predictions of Volatile Anesthetic Interactions with the Microtubule Cytoskeleton: Implications for Side Effects of General Anesthesia

Craddock, Travis J. A.; George, Marc St.; Freedman, Holly; Barakat, Khaled; Damaraju, Sambasivarao; Hameroff, Stuart R.; Tuszyński, Jack A.

doi:10.1371/journal.pone.0037251

Cited by 59 publications

(60 citation statements)

References 107 publications

(106 reference statements)

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“…This body of work suggests that propofol and other common anesthetics, such as etomidate and ketamine (10)(11)(12)(13)(14), may target additional protein networks of the CNS, including potential interactions with the cytoskeleton to contribute to the desired and undesired anesthesia end points. Some evidence for anesthetic interactions with the cytoskeleton exist (15)(16)(17)(18). For example, different classes of general anesthetics bind specifically to tubulin and alter its stability (17,18), and entire theories of anesthetic action have been constructed around microtubule (MT) properties (19).…”

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confidence: 99%

“…Some evidence for anesthetic interactions with the cytoskeleton exist (15)(16)(17)(18). For example, different classes of general anesthetics bind specifically to tubulin and alter its stability (17,18), and entire theories of anesthetic action have been constructed around microtubule (MT) properties (19). However, the molecular motors that travel along MTs have received no attention as anesthetic targets.…”

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confidence: 99%

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Common general anesthetic propofol impairs kinesin processivity

Bensel

Guzik-Lendrum

Masucci

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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Propofol is the most widely used i.v. general anesthetic to induce and maintain anesthesia. It is now recognized that this small molecule influences ligand-gated channels, including the GABA A receptor and others. Specific propofol binding sites have been mapped using photoaffinity ligands and mutagenesis; however, their precise target interaction profiles fail to provide complete mechanistic underpinnings for the anesthetic state. These results suggest that propofol and other common anesthetics, such as etomidate and ketamine, may target additional protein networks of the CNS to contribute to the desired and undesired anesthesia end points. Some evidence for anesthetic interactions with the cytoskeleton exists, but the molecular motors have received no attention as anesthetic targets. We have recently discovered that propofol inhibits conventional kinesin-1 KIF5B and kinesin-2 KIF3AB and KIF3AC, causing a significant reduction in the distances that these processive kinesins can travel. These microtubule-based motors are highly expressed in the CNS and the major anterograde transporters of cargos, such as mitochondria, synaptic vesicle precursors, neurotransmitter receptors, cell signaling and adhesion molecules, and ciliary intraflagellar transport particles. The single-molecule results presented show that the kinesin processive stepping distance decreases 40-60% with EC 50 values <100 nM propofol without an effect on velocity. The lack of a velocity effect suggests that propofol is not binding at the ATP site or allosteric sites that modulate microtubule-activated ATP turnover. Rather, we propose that a transient propofol allosteric site forms when the motor head binds to the microtubule during stepping.anesthesia | allosteric inhibitor | microtubule | etomidate | ketamine

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confidence: 99%

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confidence: 99%

Common general anesthetic propofol impairs kinesin processivity

Bensel

Guzik-Lendrum

Masucci

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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“…Several anaesthetics affect mitochondrial function, some directly inhibiting the ETC while others induce uncoupling [104,105]; they do seem to bind to key mitochondrial proteins, such as the voltage dependent anion channel (VDAC) [106] and critically, microtubules [107], which are also closely associated with mitochondria. Furthermore, anaesthetics are also being investigated as neuroprotective and cardioprotective agents, with researchers focussing on modulation of mitochondrial function as a key mode of action [108,109].…”

Section: Advanced Intelligence and Electro-magnetic Fields; A Role Fomentioning

confidence: 99%

The Hormesis of Thinking: A Deeper Quantum Thermodynamic Perspective?

Nunn¹,

Guy²,

Bell³

2017

Int J Neurorehabilitation Eng

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We are able to read this because of quantum and thermodynamic principles that via an inorganic proton gradient, possibly generated 4.2 billion years ago, gave rise to a system that has an awareness of time and space by using energy to integrate information. Life can be described as a dissipative system driven by an energy gradient that uses information to positively reinforce its self-sustaining structure, which in turn increases its non-linear decisional capacity. Key in the evolution of life has been stress coupled to natural selection, which usually meant an increased demand for energy. As hormesis describes the adaptive response to stress, we propose that hormesis embraces not only the evolution of life, but that of intelligence itself, as natural selection would favour systems that enhances its efficiency. A component of the hormetic response in eukaryotes is the mitochondrion, which itself relies on quantum effects such as tunnelling. This suggests that quantum effects control the stability of individual cells as well as long-lived cellular networks. Hormesis, which can be anti-inflammatory, is therefore key in maintaining the functional stability of complex systems, including the brain. In contrast, a lack of classical hormetic factors, such as physical activity, plant polyphenols, or calorie restriction, will lead to accelerated cognitive decline, which is associated with increased inflammation. However, there may be another previously unidentified factor that could also be considered hormetic, and that is thinking itself. Here we propose that the process of "thinking", and managing complex movement, induces "stress" in the neuronal system and is therefore in itself part of maintaining cognitive health and reserve throughout life. In effect, the right amount of thinking and information processing can beneficially induce adaptation, and this itself could be explainable by quantum thermodynamics.

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“…The estimate for the binding free energy of the complex in this study was −8.3 kcal/mol, which was in a good agreement with large system experimental value, −9.6 kcal/mol. Our group recently applied a similar approach to study various systems including ERCC1-XPF [54], ERCC1-XPA [23,55], p53-DNA [21], p53-MDM2 [56], p53-MDM4 [56], DNA polymerase beta [57,58], aurora kinase A [59], hepatitis C virus (HCV) RNA polymerase [60], HCV NS5A protein [18], microtubules [22,[61][62][63][64][65] and immune checkpoints [66].…”

Section: Normal Mode Analysismentioning

confidence: 99%