Membrane-mediated anesthesia

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Membrane-mediated anesthesia or anaesthesia (UK) is a mechanism of action that involves an anesthetic agent exerting its pharmaceutical effects primarily through interaction with the lipid bilayer membrane.

Contents

The relationship between volatile (inhalable) general anesthetics and the cellular lipid membrane has been well established since around 1900, based on the Meyer-Overton Correlation. [1] [2] [3] [4] [5] Since 1900 there have been extensive research efforts to characterize these membrane-mediated effects of anesthesia, leading to many theories but few answers. During the 1980s the focus of anesthetic research shifted from membrane lipids to membrane proteins, [5] [6] [7] where it currently remains. [8] [9] [10] [11] Accordingly, the specific membrane-mediated anesthetic effects remain mostly undiscovered. [9] [12] [13] [14] [15]

Recent research has demonstrated promising mechanisms of membrane-mediated anesthetic action for both general and Local anesthetics. These studies suggest that the anesthetic binding site in the membrane is within ordered lipids. This binding disrupts the function of the ordered lipids, forming lipid rafts that dislodge a membrane-bound phospholipase involved in a metabolic pathway that actives anesthetic-sensitive potassium channels. [15] [16] [17] Other recent studies show similar lipid-raft-specific anesthetic effects on sodium channels. [17] [18]

See Theories of general anaesthetic action for a broader discussion of purely theoretical mechanisms.

The Meyer-Overton Correlation for Anesthetics

The Meyer-Overton Correlation (Final).png

At the turn of the twentieth century, one of the most important anesthetic-based theories began to take shape. At the time, the research of both German pharmacologist Hans Horst Meyer (1899) [1] and British-Swedish physiologist Charles Ernest Overton (1901) [2] reached the same conclusion about general anesthetics and lipids:

There is a direct correlation between anesthetic agents and lipid solubility. The more lipophillic the anesthetic agent is, the more potent the anesthetic agent is. [3] [8] [18]

This principle became known as the Meyer-Overton Correlation. It originally compared the anesthetic partition coefficient in olive oil (X-axis) to the effective dose that induced anesthesia in 50% (i.e., EC50) of the tadpole research subjects (Y-axis). [1] [2] [3] [4] Modern renditions of the Meyer-Overton plot usually compare olive oil partition coefficent of the Inhalational or Intravenous drug (X-axis) to the minimum alveolar concentration (MAC) or the effective dose 50 (i.e., ED50) of the anesthetic agent (Y-axis).[ citation needed ]

Despite more than 175 years of anesthetic use and research, the exact connection between phospholipids, the bilayer membrane, and general anesthetic agents remains mostly unknown. [4] [9] [10] Accordingly, the means of membrane-mediated anesthesia remain mostly theoretical. [4] [19] [20]

The Lateral Pressure Profile Theory

The Lateral Pressure Profile theory suggests that anesthetic agents partition into the lipid bilayer, increasing the horizontal (lateral) pressure on proteins imbedded in the membrane. The added pressure causes a conformational change in protein structure, forcing the neuronal channel into an open or closed state (e.g., hyperpolarization) that generates the Inhibitory state of general anesthesia in the central nervous system (CNS). [20] [21] [ citation needed ]

This is the first hypothesis to explain the correlations of anesthetic potency with lipid bilayer structural characteristics, describing both mechanistic and thermodynamic rationale for the effects of general anesthesia.[ citation needed ]

General anesthetics

Inhaled anesthetics partition into the membrane and disrupt the function of ordered lipids. [15] Membranes, like proteins, are composed of ordered and disordered regions. [14] The ordered region of the membrane contains a palmitate binding site that drives the association of palmitoylated proteins to clusters of GM1 lipids (sometimes referred to as lipid rafts). Palmitate's binding to lipid rafts regulates the affinity of most proteins to lipid rafts. [22]

Anesthetic (orange) is shown competing with the palmitates (blue) of a palmitoylated protein (green). The displacement of the protein from the ordered lipids in the membrane (grey) renders the protein anesthetic sensitivity. The palmitate site is selective and structured similar to a protein despite being composed of lipids. APsite.v02.jpg
Anesthetic (orange) is shown competing with the palmitates (blue) of a palmitoylated protein (green). The displacement of the protein from the ordered lipids in the membrane (grey) renders the protein anesthetic sensitivity. The palmitate site is selective and structured similar to a protein despite being composed of lipids.

Inhaled anesthetics partition into the lipid membrane and disrupt the binding of palmitate to GM1 lipids (see figure). The anesthetic binds to a specific palmitate site nonspecifically. The clusters of GM1 lipids persist, but they lose their ability to bind palmitoylated proteins. [23]

PLD2

Phospholipase D2 (PLD2) is a palmitoylated protein that is activated by substrate presentation. [24] Anesthetics cause PLD2 to move from GM1 lipids, where it lacks access to its substrate, to a PIP2 domain which has abundant PLD2 substrate. [23] Animals with genetically depleted PLD2 were significantly resistant to anesthetics. The anesthetics xenon, chloroform, isofluorane, and propofol all activate PLD in cultured cells.

TREK-1

Twik-related potassium channel (TREK-1) is localized to ordered lipids through its interaction with PLD2. Displacement of the complex from GM1 lipids causes the complex to move to clusters. The product of PLD2, phosphatidic acid (PA) directly activates TREK-1. [25] The anesthetic sensitivity of TREK-1 was shown to be through PLD2, and the sensitivity could be transferred to TRAAK, an otherwise anesthetic insensitive channel. [15]

GABAAR

The membrane mediated mechanism is still being investigated. Nonetheless, the GABAAR gamma subunit is palmitoylated and the alpha subunit binds to PIP2. When the agonist GABA binds to GABAAR it causes a translocation to thin lipids near PIP2. [26] Anesthetic disruption of Palmitate mediated localization should therefore cause the channel to move the same as an agonist, but this has not yet been confirmed.

Endocytosis

Endocytosis helps regulate the time an ion channel spends on the surface of the membrane. GM1 lipids are the site of endocytosis. The anesthetics hydroxychloroquine, tetracaine, and lidocaine blocked entry of palmitoylated protein into the endocytic pathway. [27] By blocking access to GM1 lipids, anesthetics block access to endocytosis through a membrane-mediated mechanism.

Local anesthetics

Local anesthetics disrupt ordered lipid domains and this can cause PLD2 to leave a lipid raft. [16] They also disrupt protein interactions with PIP2. [27]

History

More than 100 years ago, a unifying theory of anesthesia was proposed based on the oil partition coefficient. In the 70s this concept was extended to the disruption of lipid partitioning. [28] Partitioning itself is an integral part of forming the ordered domains in the membrane, and the proposed mechanism is very close to the current thinking, but the partitioning itself is not the target of the anesthetics. At clinical concentration, the anesthetics do not inhibit lipid partitioning. [15] Rather they inhibit the order within the partition and/or compete for the palmitate binding site. Nonetheless, several of the early conceptual ideas about how disruption of lipid partitioning could affect an ion channel have merit.

Related Research Articles

General anaesthetics are often defined as compounds that induce a loss of consciousness in humans or loss of righting reflex in animals. Clinical definitions are also extended to include an induced coma that causes lack of awareness to painful stimuli, sufficient to facilitate surgical applications in clinical and veterinary practice. General anaesthetics do not act as analgesics and should also not be confused with sedatives. General anaesthetics are a structurally diverse group of compounds whose mechanisms encompass multiple biological targets involved in the control of neuronal pathways. The precise workings are the subject of some debate and ongoing research.

A transmembrane domain (TMD) is a membrane-spanning protein domain. TMDs may consist of one or several alpha-helices or a transmembrane beta barrel. Because the interior of the lipid bilayer is hydrophobic, the amino acid residues in TMDs are often hydrophobic, although proteins such as membrane pumps and ion channels can contain polar residues. TMDs vary greatly in size and hydrophobicity; they may adopt organelle-specific properties.

<span class="mw-page-title-main">Lipid-anchored protein</span> Membrane protein

Lipid-anchored proteins are proteins located on the surface of the cell membrane that are covalently attached to lipids embedded within the cell membrane. These proteins insert and assume a place in the bilayer structure of the membrane alongside the similar fatty acid tails. The lipid-anchored protein can be located on either side of the cell membrane. Thus, the lipid serves to anchor the protein to the cell membrane. They are a type of proteolipids.

<span class="mw-page-title-main">Theories of general anaesthetic action</span> How drugs induce reversible suppression of consciousness

A general anaesthetic is a drug that brings about a reversible loss of consciousness. These drugs are generally administered by an anaesthetist/anesthesiologist to induce or maintain general anaesthesia to facilitate surgery.

<span class="mw-page-title-main">Lipid raft</span> Combination in the membranes of cells

The plasma membranes of cells contain combinations of glycosphingolipids, cholesterol and protein receptors organised in glycolipoprotein lipid microdomains termed lipid rafts. Their existence in cellular membranes remains controversial. Indeed, Kervin and Overduin imply that lipid rafts are misconstrued protein islands, which they propose form through a proteolipid code. Nonetheless, it has been proposed that they are specialized membrane microdomains which compartmentalize cellular processes by serving as organising centers for the assembly of signaling molecules, allowing a closer interaction of protein receptors and their effectors to promote kinetically favorable interactions necessary for the signal transduction. Lipid rafts influence membrane fluidity and membrane protein trafficking, thereby regulating neurotransmission and receptor trafficking. Lipid rafts are more ordered and tightly packed than the surrounding bilayer, but float freely within the membrane bilayer. Although more common in the cell membrane, lipid rafts have also been reported in other parts of the cell, such as the Golgi apparatus and lysosomes.

Phosphatidic acids are anionic phospholipids important to cell signaling and direct activation of lipid-gated ion channels. Hydrolysis of phosphatidic acid gives rise to one molecule each of glycerol and phosphoric acid and two molecules of fatty acids. They constitute about 0.25% of phospholipids in the bilayer.

<span class="mw-page-title-main">Phosphoinositide phospholipase C</span>

Phosphoinositide phospholipase C is a family of eukaryotic intracellular enzymes that play an important role in signal transduction processes. These enzymes belong to a larger superfamily of Phospholipase C. Other families of phospholipase C enzymes have been identified in bacteria and trypanosomes. Phospholipases C are phosphodiesterases.

<span class="mw-page-title-main">Phosphatidylinositol 4,5-bisphosphate</span> Chemical compound

Phosphatidylinositol 4,5-bisphosphate or PtdIns(4,5)P2, also known simply as PIP2 or PI(4,5)P2, is a minor phospholipid component of cell membranes. PtdIns(4,5)P2 is enriched at the plasma membrane where it is a substrate for a number of important signaling proteins. PIP2 also forms lipid clusters that sort proteins.

<span class="mw-page-title-main">Lipid signaling</span> Biological signaling using lipid molecules

Lipid signaling, broadly defined, refers to any biological cell signaling event involving a lipid messenger that binds a protein target, such as a receptor, kinase or phosphatase, which in turn mediate the effects of these lipids on specific cellular responses. Lipid signaling is thought to be qualitatively different from other classical signaling paradigms because lipids can freely diffuse through membranes. One consequence of this is that lipid messengers cannot be stored in vesicles prior to release and so are often biosynthesized "on demand" at their intended site of action. As such, many lipid signaling molecules cannot circulate freely in solution but, rather, exist bound to special carrier proteins in serum.

<span class="mw-page-title-main">Cholera toxin</span> Protein complex secreted by the bacterium Vibrio cholerae

Cholera toxin is an AB5 multimeric protein complex secreted by the bacterium Vibrio cholerae. CTX is responsible for the massive, watery diarrhea characteristic of cholera infection. It is a member of the heat-labile enterotoxin family.

Phospholipase D (EC 3.1.4.4, lipophosphodiesterase II, lecithinase D, choline phosphatase, PLD; systematic name phosphatidylcholine phosphatidohydrolase) is an anesthetic sensitive and mechanosensitive enzyme of the phospholipase superfamily that catalyses the following reaction

<span class="mw-page-title-main">Palmitoylation</span> Attachment of a palmitoyl group (fatty acid) to a protein

In molecular biology, palmitoylation is the covalent attachment of fatty acids, such as palmitic acid, to cysteine (S-palmitoylation) and less frequently to serine and threonine (O-palmitoylation) residues of proteins, which are typically membrane proteins. The precise function of palmitoylation depends on the particular protein being considered. Palmitoylation enhances the hydrophobicity of proteins and contributes to their membrane association. Palmitoylation also appears to play a significant role in subcellular trafficking of proteins between membrane compartments, as well as in modulating protein–protein interactions.

<span class="mw-page-title-main">PLD2</span> Protein-coding gene in the species Homo sapiens

Phospholipase D2 is an enzyme that in humans is encoded by the PLD2 gene.

<span class="mw-page-title-main">KCNK2</span> Protein-coding gene in the species Homo sapiens

Potassium channel subfamily K member 2, also known as TREK-1, is a protein that in humans is encoded by the KCNK2 gene.

<span class="mw-page-title-main">Channel blocker</span> Molecule able to block protein channels, frequently used as pharmaceutical

A channel blocker is the biological mechanism in which a particular molecule is used to prevent the opening of ion channels in order to produce a physiological response in a cell. Channel blocking is conducted by different types of molecules, such as cations, anions, amino acids, and other chemicals. These blockers act as ion channel antagonists, preventing the response that is normally provided by the opening of the channel.

<span class="mw-page-title-main">Lipid-gated ion channels</span> Type of ion channel transmembrane protein

Lipid-gated ion channels are a class of ion channels whose conductance of ions through the membrane depends directly on lipids. Classically the lipids are membrane resident anionic signaling lipids that bind to the transmembrane domain on the inner leaflet of the plasma membrane with properties of a classic ligand. Other classes of lipid-gated channels include the mechanosensitive ion channels that respond to lipid tension, thickness, and hydrophobic mismatch. A lipid ligand differs from a lipid cofactor in that a ligand derives its function by dissociating from the channel while a cofactor typically derives its function by remaining bound.

In molecular biology, substrate presentation is a biological process that activates a protein. The protein is sequestered away from its substrate and then activated by release and exposure to its substrate. A substrate is typically the substance on which an enzyme acts but can also be a protein surface to which a ligand binds. In the case of an interaction with an enzyme, the protein or organic substrate typically changes chemical form. Substrate presentation differs from allosteric regulation in that the enzyme need not change its conformation to begin catalysis. Substrate presentation is best described for domain partitioning at nanoscopic distances (<100 nm).

Palmitate mediated localization is a biological process that trafficks a palmitoylated protein to ordered lipid domains.

<span class="mw-page-title-main">Cholesterol signaling</span>

Cholesterol is a cell signaling molecule that is highly regulated in eukaryotic cell membranes. In human health, its effects are most notable in inflammation, metabolic syndrome, and neurodegeneration. At the molecular level, cholesterol primarily signals by regulating clustering of saturated lipids and proteins that depend on spatial biology and clustering for their regulation.

PIP2 domains are a type of cholesterol-independent lipid domain formed from phosphatidylinositol and positively charged proteins in the plasma membrane. They tend to inhibit GM1 lipid raft function.

References

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