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A pressure-reversible cellular mechanism of general anesthetics capable of altering a possible mechanism for consciousness.

Vadakkan KI - Springerplus (2015)

Bottom Line: Anesthetic requirement is reduced in the presence of dopamine that causes enlargement of dendritic spines.The pressure gradient reduce solubility and displace anesthetic molecules from the membranes into the paravenular space, explaining the pressure reversal of anesthesia.The common mechanism of anesthetics presented here can operate along with the known specific actions of different anesthetics.

View Article: PubMed Central - PubMed

Affiliation: Division of Neurology, Department of Medicine, University of Toronto, Sunnybrook Health Sciences Centre, 2075 Bayview Avenue, Room A4-08, Toronto, ON M4N 3M5 Canada.

ABSTRACT
Different anesthetics are known to modulate different types of membrane-bound receptors. Their common mechanism of action is expected to alter the mechanism for consciousness. Consciousness is hypothesized as the integral of all the units of internal sensations induced by reactivation of inter-postsynaptic membrane functional LINKs during mechanisms that lead to oscillating potentials. The thermodynamics of the spontaneous lateral curvature of lipid membranes induced by lipophilic anesthetics can lead to the formation of non-specific inter-postsynaptic membrane functional LINKs by different mechanisms. These include direct membrane contact by excluding the inter-membrane hydrophilic region and readily reversible partial membrane hemifusion. The constant reorganization of the lipid membranes at the lateral edges of the postsynaptic terminals (dendritic spines) resulting from AMPA receptor-subunit vesicle exocytosis and endocytosis can favor the effect of anesthetic molecules on lipid membranes at this location. Induction of a large number of non-specific LINKs can alter the conformation of the integral of the units of internal sensations that maintain consciousness. Anesthetic requirement is reduced in the presence of dopamine that causes enlargement of dendritic spines. Externally applied pressure can transduce from the middle ear through the perilymph, cerebrospinal fluid, and the recently discovered glymphatic pathway to the extracellular matrix space, and finally to the paravenular space. The pressure gradient reduce solubility and displace anesthetic molecules from the membranes into the paravenular space, explaining the pressure reversal of anesthesia. Changes in membrane composition and the conversion of membrane hemifusion to fusion due to defects in the checkpoint mechanisms can lead to cytoplasmic content mixing between neurons and cause neurodegenerative changes. The common mechanism of anesthetics presented here can operate along with the known specific actions of different anesthetics.

No MeSH data available.


Related in: MedlinePlus

Formation and reactivation of inter-postsynaptic functional LINKs. a The illustration shows functional LINK formation between two postsynaptic membranes (postsynapses or dendritic spines) B and D when they are simultaneously activated when two stimuli are associated. The functional LINK is reversible, stabilizable and its formation is a function of the simultaneous activation of postsynapses B and D. A and C are corresponding presynaptic terminals. b At a later time, when one of the stimuli arrives at postsynapse B through synapse A–B, functional LINK B–D is re-activated, resulting in the activation of postsynaptic membrane D. This induces a unit of internal sensation of activity arriving from presynaptic terminal C. The reactivation of the functional LINK is a function of arrival of activity at one of the postsynaptic terminals. c Two abutted synapses are shown with their presynaptic and postsynaptic terminal membranes in lipid bilayers. Note that the postsynaptic membranes are separated by extracellular matrix space. d The formed inter-postsynaptic functional LINK is shown in red. Both direct membrane contact by excluding inter-membrane hydrophilic region and reversible partial membrane hemifusion are common mechanisms (Figure modified from Vadakkan 2010)
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Fig1: Formation and reactivation of inter-postsynaptic functional LINKs. a The illustration shows functional LINK formation between two postsynaptic membranes (postsynapses or dendritic spines) B and D when they are simultaneously activated when two stimuli are associated. The functional LINK is reversible, stabilizable and its formation is a function of the simultaneous activation of postsynapses B and D. A and C are corresponding presynaptic terminals. b At a later time, when one of the stimuli arrives at postsynapse B through synapse A–B, functional LINK B–D is re-activated, resulting in the activation of postsynaptic membrane D. This induces a unit of internal sensation of activity arriving from presynaptic terminal C. The reactivation of the functional LINK is a function of arrival of activity at one of the postsynaptic terminals. c Two abutted synapses are shown with their presynaptic and postsynaptic terminal membranes in lipid bilayers. Note that the postsynaptic membranes are separated by extracellular matrix space. d The formed inter-postsynaptic functional LINK is shown in red. Both direct membrane contact by excluding inter-membrane hydrophilic region and reversible partial membrane hemifusion are common mechanisms (Figure modified from Vadakkan 2010)

Mentions: Potentials arriving at the postsynaptic terminal through a LINK (the word “link” is highlighted to emphasize its importance) from the neighboring postsynaptic terminal can evoke units of internal sensations eliciting the semblance of the arrival of activity from the presynaptic terminal. An inter-postsynaptic functional LINK is expected to form between the abutted postsynaptic locations as a function of the simultaneous arrival of activity from two different sensory inputs during associative learning between two stimuli (Fig. 1a). The reactivation of the LINK occurs as a function of the arrival of activity from the one of the associatively learned stimuli through the inter-postsynaptic functional LINK to the inter-LINKed postsynaptic terminal (Fig. 1b). Since lipid bilayers of different postsynaptic terminals (Fig. 1c) abut each other with a negligible extracellular matrix volume, as visualized in electron microscopic pictures, an interaction between their outer layers is expected to occur (Fig. 1d). The sensory identity of the semblance of the second stimulus formed at a postsynaptic terminal by the reactivation of the inter-postsynaptic functional LINK by the arrival of activity from the first stimulus and how it can be derived are explained in Fig. 2.Fig. 1


A pressure-reversible cellular mechanism of general anesthetics capable of altering a possible mechanism for consciousness.

Vadakkan KI - Springerplus (2015)

Formation and reactivation of inter-postsynaptic functional LINKs. a The illustration shows functional LINK formation between two postsynaptic membranes (postsynapses or dendritic spines) B and D when they are simultaneously activated when two stimuli are associated. The functional LINK is reversible, stabilizable and its formation is a function of the simultaneous activation of postsynapses B and D. A and C are corresponding presynaptic terminals. b At a later time, when one of the stimuli arrives at postsynapse B through synapse A–B, functional LINK B–D is re-activated, resulting in the activation of postsynaptic membrane D. This induces a unit of internal sensation of activity arriving from presynaptic terminal C. The reactivation of the functional LINK is a function of arrival of activity at one of the postsynaptic terminals. c Two abutted synapses are shown with their presynaptic and postsynaptic terminal membranes in lipid bilayers. Note that the postsynaptic membranes are separated by extracellular matrix space. d The formed inter-postsynaptic functional LINK is shown in red. Both direct membrane contact by excluding inter-membrane hydrophilic region and reversible partial membrane hemifusion are common mechanisms (Figure modified from Vadakkan 2010)
© Copyright Policy - OpenAccess
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4561946&req=5

Fig1: Formation and reactivation of inter-postsynaptic functional LINKs. a The illustration shows functional LINK formation between two postsynaptic membranes (postsynapses or dendritic spines) B and D when they are simultaneously activated when two stimuli are associated. The functional LINK is reversible, stabilizable and its formation is a function of the simultaneous activation of postsynapses B and D. A and C are corresponding presynaptic terminals. b At a later time, when one of the stimuli arrives at postsynapse B through synapse A–B, functional LINK B–D is re-activated, resulting in the activation of postsynaptic membrane D. This induces a unit of internal sensation of activity arriving from presynaptic terminal C. The reactivation of the functional LINK is a function of arrival of activity at one of the postsynaptic terminals. c Two abutted synapses are shown with their presynaptic and postsynaptic terminal membranes in lipid bilayers. Note that the postsynaptic membranes are separated by extracellular matrix space. d The formed inter-postsynaptic functional LINK is shown in red. Both direct membrane contact by excluding inter-membrane hydrophilic region and reversible partial membrane hemifusion are common mechanisms (Figure modified from Vadakkan 2010)
Mentions: Potentials arriving at the postsynaptic terminal through a LINK (the word “link” is highlighted to emphasize its importance) from the neighboring postsynaptic terminal can evoke units of internal sensations eliciting the semblance of the arrival of activity from the presynaptic terminal. An inter-postsynaptic functional LINK is expected to form between the abutted postsynaptic locations as a function of the simultaneous arrival of activity from two different sensory inputs during associative learning between two stimuli (Fig. 1a). The reactivation of the LINK occurs as a function of the arrival of activity from the one of the associatively learned stimuli through the inter-postsynaptic functional LINK to the inter-LINKed postsynaptic terminal (Fig. 1b). Since lipid bilayers of different postsynaptic terminals (Fig. 1c) abut each other with a negligible extracellular matrix volume, as visualized in electron microscopic pictures, an interaction between their outer layers is expected to occur (Fig. 1d). The sensory identity of the semblance of the second stimulus formed at a postsynaptic terminal by the reactivation of the inter-postsynaptic functional LINK by the arrival of activity from the first stimulus and how it can be derived are explained in Fig. 2.Fig. 1

Bottom Line: Anesthetic requirement is reduced in the presence of dopamine that causes enlargement of dendritic spines.The pressure gradient reduce solubility and displace anesthetic molecules from the membranes into the paravenular space, explaining the pressure reversal of anesthesia.The common mechanism of anesthetics presented here can operate along with the known specific actions of different anesthetics.

View Article: PubMed Central - PubMed

Affiliation: Division of Neurology, Department of Medicine, University of Toronto, Sunnybrook Health Sciences Centre, 2075 Bayview Avenue, Room A4-08, Toronto, ON M4N 3M5 Canada.

ABSTRACT
Different anesthetics are known to modulate different types of membrane-bound receptors. Their common mechanism of action is expected to alter the mechanism for consciousness. Consciousness is hypothesized as the integral of all the units of internal sensations induced by reactivation of inter-postsynaptic membrane functional LINKs during mechanisms that lead to oscillating potentials. The thermodynamics of the spontaneous lateral curvature of lipid membranes induced by lipophilic anesthetics can lead to the formation of non-specific inter-postsynaptic membrane functional LINKs by different mechanisms. These include direct membrane contact by excluding the inter-membrane hydrophilic region and readily reversible partial membrane hemifusion. The constant reorganization of the lipid membranes at the lateral edges of the postsynaptic terminals (dendritic spines) resulting from AMPA receptor-subunit vesicle exocytosis and endocytosis can favor the effect of anesthetic molecules on lipid membranes at this location. Induction of a large number of non-specific LINKs can alter the conformation of the integral of the units of internal sensations that maintain consciousness. Anesthetic requirement is reduced in the presence of dopamine that causes enlargement of dendritic spines. Externally applied pressure can transduce from the middle ear through the perilymph, cerebrospinal fluid, and the recently discovered glymphatic pathway to the extracellular matrix space, and finally to the paravenular space. The pressure gradient reduce solubility and displace anesthetic molecules from the membranes into the paravenular space, explaining the pressure reversal of anesthesia. Changes in membrane composition and the conversion of membrane hemifusion to fusion due to defects in the checkpoint mechanisms can lead to cytoplasmic content mixing between neurons and cause neurodegenerative changes. The common mechanism of anesthetics presented here can operate along with the known specific actions of different anesthetics.

No MeSH data available.


Related in: MedlinePlus