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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 of different types of reversible inter-postsynaptic functional LINKs. a Two abutted synapses A–B and C–D. Presynaptic terminals A and C are shown with synaptic vesicles (in blue color). Action potential arrives at presynaptic terminal A releasing a volley of neurotransmitters from many synaptic vesicles inducing an excitatory postsynaptic potential (EPSP) at postsynaptic terminal B. The waveform represents the direction towards which the EPSP propagates. From the presynaptic terminal C, one vesicle is shown to release its contents to the synaptic cleft. This quantal release is a continuous process (even during rest) providing very small potentials to postsynaptic membrane D. Postsynaptic terminals B and D have membrane-bound vesicles marked V inside them. These vesicles contain glutamate receptor subtype 1 (GluA1). Activity arriving at the synapse can lead to exocytosis of GluA1 receptor-subunits and expansion of the postsynaptic membrane. During exocytosis, the vesicle membrane is added to the postsynaptic membrane at locations of exocytosis making this region of the membrane highly re-organisable. This matches with the location where α-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid (AMPA) receptor subunits were shown to concentrate at the extra-synaptic locations extending at least 25 nm beyond the synaptic specialization (Jacob and Weinberg 2014). Note the presence of a hydrophilic region separating postsynaptic terminals B and D. When action potential arrives at the presynaptic terminal, it activates synapse A–B and an EPSP is induced at postsynaptic terminal B. The hydrophilic region prevents any type of interaction between postsynapses B and D. Very high energy is required for excluding the inter-postsynaptic hydrophilic region (Martens and McMahon 2008). b Diagram showing the effect of lipophilic anesthetic molecule on the membranes. Incorporation of the hydrophobic anesthetic molecule to the lipid membrane especially at the re-organisable areas that lead to membrane expansion at these locations can provide sufficient energy to exclude the inter-postsynaptic hydrophilic region allowing close contact between the postsynaptic membranes at this region. Action potential arriving at synapse A–B reactivates the inter-postsynaptic functional LINK formed by close inter-postsynaptic contact and spreads to postsynaptic terminal D. an membrane segment marked in Turkish blue shows area where membrane reorganization occurs and anesthetic molecules lead to membrane expansion. Formation of large number of non-specific inter-postsynaptic functional LINKs disturbs the net C-semblance formation explained in Fig. 4 leading to loss of consciousness. When the anesthetic molecule is removed, the process reverses back. c Diagram showing formation of a partial inter-postsynaptic membrane hemifusion following anesthesia. Note the interaction between the outer layers of membranes of the postsynaptic terminals. Depending on the lipid membrane composition and the type and concentration of anesthetics, the process of close contact between the membranes described in above section (b) can get converted to a partial hemifusion state. The process can even advance to a reversible complete hemifusion state as described in Fig. 8b depending on several factors. When the anesthetic molecule is removed, the hemifusion reverses back
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Fig5: Formation of different types of reversible inter-postsynaptic functional LINKs. a Two abutted synapses A–B and C–D. Presynaptic terminals A and C are shown with synaptic vesicles (in blue color). Action potential arrives at presynaptic terminal A releasing a volley of neurotransmitters from many synaptic vesicles inducing an excitatory postsynaptic potential (EPSP) at postsynaptic terminal B. The waveform represents the direction towards which the EPSP propagates. From the presynaptic terminal C, one vesicle is shown to release its contents to the synaptic cleft. This quantal release is a continuous process (even during rest) providing very small potentials to postsynaptic membrane D. Postsynaptic terminals B and D have membrane-bound vesicles marked V inside them. These vesicles contain glutamate receptor subtype 1 (GluA1). Activity arriving at the synapse can lead to exocytosis of GluA1 receptor-subunits and expansion of the postsynaptic membrane. During exocytosis, the vesicle membrane is added to the postsynaptic membrane at locations of exocytosis making this region of the membrane highly re-organisable. This matches with the location where α-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid (AMPA) receptor subunits were shown to concentrate at the extra-synaptic locations extending at least 25 nm beyond the synaptic specialization (Jacob and Weinberg 2014). Note the presence of a hydrophilic region separating postsynaptic terminals B and D. When action potential arrives at the presynaptic terminal, it activates synapse A–B and an EPSP is induced at postsynaptic terminal B. The hydrophilic region prevents any type of interaction between postsynapses B and D. Very high energy is required for excluding the inter-postsynaptic hydrophilic region (Martens and McMahon 2008). b Diagram showing the effect of lipophilic anesthetic molecule on the membranes. Incorporation of the hydrophobic anesthetic molecule to the lipid membrane especially at the re-organisable areas that lead to membrane expansion at these locations can provide sufficient energy to exclude the inter-postsynaptic hydrophilic region allowing close contact between the postsynaptic membranes at this region. Action potential arriving at synapse A–B reactivates the inter-postsynaptic functional LINK formed by close inter-postsynaptic contact and spreads to postsynaptic terminal D. an membrane segment marked in Turkish blue shows area where membrane reorganization occurs and anesthetic molecules lead to membrane expansion. Formation of large number of non-specific inter-postsynaptic functional LINKs disturbs the net C-semblance formation explained in Fig. 4 leading to loss of consciousness. When the anesthetic molecule is removed, the process reverses back. c Diagram showing formation of a partial inter-postsynaptic membrane hemifusion following anesthesia. Note the interaction between the outer layers of membranes of the postsynaptic terminals. Depending on the lipid membrane composition and the type and concentration of anesthetics, the process of close contact between the membranes described in above section (b) can get converted to a partial hemifusion state. The process can even advance to a reversible complete hemifusion state as described in Fig. 8b depending on several factors. When the anesthetic molecule is removed, the hemifusion reverses back

Mentions: Different candidate mechanisms for the inter-postsynaptic functional LINK include direct membrane contact excluding the inter-membrane hydrophilic region, reversible partial and complete membrane hemifusion (Vadakkan 2013) and a still unknown mechanism operating through the ECM. The hydration repulsive force between two artificial lipid membranes maintains a distance of nearly 2 nm between the membranes (Markin et al. 1984). Diminishing the inter-membrane hydration repulsion is one of the methods of initiating membrane contact (Rand and Parsegian 1989). The direct membrane contact excluding the inter-membrane hydrophilic region is an ideal mechanism due to its rapid reversibility. Membrane dynamics at the postsynaptic membrane very close to the synapse is a favorable location for achieving direct membrane contact by excluding the inter-membrane hydrophilic region (Fig. 5a, b).Fig. 5


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

Vadakkan KI - Springerplus (2015)

Formation of different types of reversible inter-postsynaptic functional LINKs. a Two abutted synapses A–B and C–D. Presynaptic terminals A and C are shown with synaptic vesicles (in blue color). Action potential arrives at presynaptic terminal A releasing a volley of neurotransmitters from many synaptic vesicles inducing an excitatory postsynaptic potential (EPSP) at postsynaptic terminal B. The waveform represents the direction towards which the EPSP propagates. From the presynaptic terminal C, one vesicle is shown to release its contents to the synaptic cleft. This quantal release is a continuous process (even during rest) providing very small potentials to postsynaptic membrane D. Postsynaptic terminals B and D have membrane-bound vesicles marked V inside them. These vesicles contain glutamate receptor subtype 1 (GluA1). Activity arriving at the synapse can lead to exocytosis of GluA1 receptor-subunits and expansion of the postsynaptic membrane. During exocytosis, the vesicle membrane is added to the postsynaptic membrane at locations of exocytosis making this region of the membrane highly re-organisable. This matches with the location where α-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid (AMPA) receptor subunits were shown to concentrate at the extra-synaptic locations extending at least 25 nm beyond the synaptic specialization (Jacob and Weinberg 2014). Note the presence of a hydrophilic region separating postsynaptic terminals B and D. When action potential arrives at the presynaptic terminal, it activates synapse A–B and an EPSP is induced at postsynaptic terminal B. The hydrophilic region prevents any type of interaction between postsynapses B and D. Very high energy is required for excluding the inter-postsynaptic hydrophilic region (Martens and McMahon 2008). b Diagram showing the effect of lipophilic anesthetic molecule on the membranes. Incorporation of the hydrophobic anesthetic molecule to the lipid membrane especially at the re-organisable areas that lead to membrane expansion at these locations can provide sufficient energy to exclude the inter-postsynaptic hydrophilic region allowing close contact between the postsynaptic membranes at this region. Action potential arriving at synapse A–B reactivates the inter-postsynaptic functional LINK formed by close inter-postsynaptic contact and spreads to postsynaptic terminal D. an membrane segment marked in Turkish blue shows area where membrane reorganization occurs and anesthetic molecules lead to membrane expansion. Formation of large number of non-specific inter-postsynaptic functional LINKs disturbs the net C-semblance formation explained in Fig. 4 leading to loss of consciousness. When the anesthetic molecule is removed, the process reverses back. c Diagram showing formation of a partial inter-postsynaptic membrane hemifusion following anesthesia. Note the interaction between the outer layers of membranes of the postsynaptic terminals. Depending on the lipid membrane composition and the type and concentration of anesthetics, the process of close contact between the membranes described in above section (b) can get converted to a partial hemifusion state. The process can even advance to a reversible complete hemifusion state as described in Fig. 8b depending on several factors. When the anesthetic molecule is removed, the hemifusion reverses back
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Fig5: Formation of different types of reversible inter-postsynaptic functional LINKs. a Two abutted synapses A–B and C–D. Presynaptic terminals A and C are shown with synaptic vesicles (in blue color). Action potential arrives at presynaptic terminal A releasing a volley of neurotransmitters from many synaptic vesicles inducing an excitatory postsynaptic potential (EPSP) at postsynaptic terminal B. The waveform represents the direction towards which the EPSP propagates. From the presynaptic terminal C, one vesicle is shown to release its contents to the synaptic cleft. This quantal release is a continuous process (even during rest) providing very small potentials to postsynaptic membrane D. Postsynaptic terminals B and D have membrane-bound vesicles marked V inside them. These vesicles contain glutamate receptor subtype 1 (GluA1). Activity arriving at the synapse can lead to exocytosis of GluA1 receptor-subunits and expansion of the postsynaptic membrane. During exocytosis, the vesicle membrane is added to the postsynaptic membrane at locations of exocytosis making this region of the membrane highly re-organisable. This matches with the location where α-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid (AMPA) receptor subunits were shown to concentrate at the extra-synaptic locations extending at least 25 nm beyond the synaptic specialization (Jacob and Weinberg 2014). Note the presence of a hydrophilic region separating postsynaptic terminals B and D. When action potential arrives at the presynaptic terminal, it activates synapse A–B and an EPSP is induced at postsynaptic terminal B. The hydrophilic region prevents any type of interaction between postsynapses B and D. Very high energy is required for excluding the inter-postsynaptic hydrophilic region (Martens and McMahon 2008). b Diagram showing the effect of lipophilic anesthetic molecule on the membranes. Incorporation of the hydrophobic anesthetic molecule to the lipid membrane especially at the re-organisable areas that lead to membrane expansion at these locations can provide sufficient energy to exclude the inter-postsynaptic hydrophilic region allowing close contact between the postsynaptic membranes at this region. Action potential arriving at synapse A–B reactivates the inter-postsynaptic functional LINK formed by close inter-postsynaptic contact and spreads to postsynaptic terminal D. an membrane segment marked in Turkish blue shows area where membrane reorganization occurs and anesthetic molecules lead to membrane expansion. Formation of large number of non-specific inter-postsynaptic functional LINKs disturbs the net C-semblance formation explained in Fig. 4 leading to loss of consciousness. When the anesthetic molecule is removed, the process reverses back. c Diagram showing formation of a partial inter-postsynaptic membrane hemifusion following anesthesia. Note the interaction between the outer layers of membranes of the postsynaptic terminals. Depending on the lipid membrane composition and the type and concentration of anesthetics, the process of close contact between the membranes described in above section (b) can get converted to a partial hemifusion state. The process can even advance to a reversible complete hemifusion state as described in Fig. 8b depending on several factors. When the anesthetic molecule is removed, the hemifusion reverses back
Mentions: Different candidate mechanisms for the inter-postsynaptic functional LINK include direct membrane contact excluding the inter-membrane hydrophilic region, reversible partial and complete membrane hemifusion (Vadakkan 2013) and a still unknown mechanism operating through the ECM. The hydration repulsive force between two artificial lipid membranes maintains a distance of nearly 2 nm between the membranes (Markin et al. 1984). Diminishing the inter-membrane hydration repulsion is one of the methods of initiating membrane contact (Rand and Parsegian 1989). The direct membrane contact excluding the inter-membrane hydrophilic region is an ideal mechanism due to its rapid reversibility. Membrane dynamics at the postsynaptic membrane very close to the synapse is a favorable location for achieving direct membrane contact by excluding the inter-membrane hydrophilic region (Fig. 5a, b).Fig. 5

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