The endocannabinoid transporters (eCBTs) are

transport protein A transport protein (variously referred to as a transmembrane pump, transporter, escort protein, acid transport protein, cation transport protein, or anion transport protein) is a protein that serves the function of moving other materials within ...

s for the

endocannabinoid Cannabinoids () are several structural classes of compounds found primarily in the ''Cannabis'' plant or as synthetic compounds. The most notable cannabinoid is the phytocannabinoid tetrahydrocannabinol (THC) (delta-9-THC), the primary psychoact ...

s. Most

neurotransmitter A neurotransmitter is a signaling molecule secreted by a neuron to affect another cell across a Chemical synapse, synapse. The cell receiving the signal, or target cell, may be another neuron, but could also be a gland or muscle cell. Neurotra ...

s are water-soluble and require

transmembrane protein A transmembrane protein is a type of integral membrane protein that spans the entirety of the cell membrane. Many transmembrane proteins function as gateways to permit the transport of specific substances across the membrane. They frequently un ...

s to transport them across the

cell membrane The cell membrane (also known as the plasma membrane or cytoplasmic membrane, and historically referred to as the plasmalemma) is a biological membrane that separates and protects the interior of a cell from the outside environment (the extr ...

. The endocannabinoids (

anandamide Anandamide (ANA), also referred to as ''N''-arachidonoylethanolamine (AEA) is a fatty acid neurotransmitter belonging to the fatty acid derivative group known as N-acylethanolamine (NAE). Anandamide takes its name from the Sanskrit word ''ananda ...

, AEA, and

2-arachidonoylglycerol 2-Arachidonoylglycerol (2-AG) is an endocannabinoid, an endogenous agonist of the CB1 receptor and the primary endogenous ligand for the CB2 receptor. It is an ester formed from the omega-6 fatty acid arachidonic acid and glycerol. It is pres ...

, 2-AG) on the other hand, are non-charged lipids that readily cross lipid membranes. However, since the endocannabinoids are water

immiscible Miscibility () is the property of two chemical substance, substances to mix in all mixing ratio, proportions (that is, to fully dissolution (chemistry), dissolve in each other at any concentration), forming a homogeneity and heterogeneity, homoge ...

, protein transporters have been described that act as carriers to

solubilize Micellar solubilization (solubilization) is the process of incorporating the solubilizate (the component that undergoes solubilization) into or onto micelles. Solubilization may occur in a system consisting of a solvent, an association colloid (a ...

and transport the endocannabinoids through the aqueous

cytoplasm The cytoplasm describes all the material within a eukaryotic or prokaryotic cell, enclosed by the cell membrane, including the organelles and excluding the nucleus in eukaryotic cells. The material inside the nucleus of a eukaryotic cell a ...

. These include the

heat shock protein Heat shock proteins (HSPs) are a family of proteins produced by cells in response to exposure to stressful conditions. They were first described in relation to heat shock, but are now known to also be expressed during other stresses including ex ...

s (

Hsp70 The 70 kilodalton heat shock proteins (Hsp70s or DnaK) are a family of conserved ubiquitously expressed heat shock proteins. Proteins with similar structure exist in virtually all living organisms and play crucial roles in the development of can ...

s) and

fatty acid-binding protein The fatty-acid-binding proteins (FABPs) are a family of transport proteins for fatty acids and other lipophilic substances such as eicosanoids and retinoids. These proteins are thought to facilitate the transfer of fatty acids between extra- and i ...

s for anandamide (FABPs). FABPs such as FABP1, FABP3, FABP5, and FABP7 have been shown to bind endocannabinoids. FABP inhibitors attenuate the breakdown of anandamide by the

enzyme An enzyme () is a protein that acts as a biological catalyst by accelerating chemical reactions. The molecules upon which enzymes may act are called substrate (chemistry), substrates, and the enzyme converts the substrates into different mol ...

fatty acid amide hydrolase Fatty-acid amide hydrolase 1 (FAAH) is a member of the serine hydrolase family of enzymes. It was first shown to break down anandamide (AEA), an ''N''-acylethanolamine (NAE) in 1993. In humans, it is encoded by the gene ''FAAH''.; Function ...

(FAAH) in cell culture. One of these inhibitors (SB-FI-26), isolated from a virtual library of a million compounds, belongs to a class of compounds (named the "truxilloids') that act as an anti-nociceptive agent with mild

anti-inflammatory Anti-inflammatory is the property of a substance or treatment that reduces inflammation, fever or swelling. Anti-inflammatory drugs, also called anti-inflammatories, make up about half of analgesics. These drugs reduce pain by inhibiting mechan ...

activity in mice. These

truxillic acid Truxillic acids are any of several crystalline stereoisomeric cyclic dicarboxylic acids with the formula (C6H5C2H2(CO2H)2. They are colorless solids. These compounds are obtained by the + 2photocycloadditions of cinnamic acid where the two tra ...

s and their derivatives have been known to have anti-inflammatory and anti-nociceptive effects in mice and are active components of a Chinese herbal medicine ((−)-Incarvillateine

Incarvillea ''Incarvillea'' is a genus of about 16 species''Incarvillea''.
Flora of China. ...

sinensis) used to treat

rheumatism Rheumatism or rheumatic disorders are conditions causing chronic, often intermittent pain affecting the joints or connective tissue. Rheumatism does not designate any specific disorder, but covers at least 200 different conditions, including a ...

and pain in human. The blockade of anandamide transport may, at least in part, be the mechanism through which these compounds exert their anti-nociceptive effects. Studies have found the involvement of

cholesterol Cholesterol is the principal sterol of all higher animals, distributed in body Tissue (biology), tissues, especially the brain and spinal cord, and in Animal fat, animal fats and oils. Cholesterol is biosynthesis, biosynthesized by all anima ...

in membrane uptake and transport of anandamide. Cholesterol stimulates both the insertion of anandamide into synthetic lipid monolayers and bilayers, and its transport across bilayer membranes, suggest that besides putative anandamide protein-transporters, cholesterol could be an important component of the anandamide transport machinery, and as cholesterol-dependent modulation of CB1

cannabinoid receptor Cannabinoid receptors, located throughout the body, are part of the endocannabinoid system of vertebrates a class of cell membrane receptors in the G protein-coupled receptor superfamily. As is typical of G protein-coupled receptors, the cann ...

s in

nerve cells A neuron (American English), neurone (British English), or nerve cell, is an excitable cell that fires electric signals called action potentials across a neural network in the nervous system. They are located in the nervous system and help to ...

. The catalytic efficiency (i.e., the ratio between maximal velocity and Michaelis–Menten constant) of the AEA membrane transporter (AMT) is almost doubled compared with control cells, demonstrate that, among the proteins of the “endocannabinoid system,” only CB1 and AMT critically depend on membrane cholesterol content, an observation that may have important implications for the role of CB1 in protecting nerve cells against (endo)cannabinoid-induced

apoptosis Apoptosis (from ) is a form of programmed cell death that occurs in multicellular organisms and in some eukaryotic, single-celled microorganisms such as yeast. Biochemistry, Biochemical events lead to characteristic cell changes (Morphology (biol ...

. This can be a reason, why the use of drugs to lower cholesterol is tied to a higher depression risk, and the correlation between levels and increased

death Death is the end of life; the irreversible cessation of all biological functions that sustain a living organism. Death eventually and inevitably occurs in all organisms. The remains of a former organism normally begin to decompose sh ...

rates from

suicide Suicide is the act of intentionally causing one's own death. Risk factors for suicide include mental disorders, physical disorders, and substance abuse. Some suicides are impulsive acts driven by stress (such as from financial or ac ...

and other

violent Violence is characterized as the use of physical force by humans to cause harm to other living beings, or property, such as pain, injury, disablement, death, damage and destruction. The World Health Organization (WHO) defines violence a ...

causes. Activation of CB1 enhances AMT activity through increased

nitric oxide synthase Nitric oxide synthases (NOSs) are a family of enzymes catalyzing the production of nitric oxide (NO) from L-arginine. NO is an important cellular signaling molecule. It helps modulate vascular tone, insulin secretion, airway tone, and peristal ...

(NOS) activity and subsequent increase of NO production, whereas AMT activity instead is reduced by activation of the CB2 cannabinoid receptor, which inhibits NOS and NO release, also suggesting the distribution of these receptors may drive AEA directional transport through the

blood–brain barrier The blood–brain barrier (BBB) is a highly selective semipermeable membrane, semipermeable border of endothelium, endothelial cells that regulates the transfer of solutes and chemicals between the circulatory system and the central nervous system ...

and other

endothelial cells The endothelium (: endothelia) is a single layer of squamous endothelial cells that line the interior surface of blood vessels and lymphatic vessels. The endothelium forms an interface between circulating blood or lymph in the lumen and the res ...

. As reviewed in 2016; "Many of the AMT (EMT) proposals have fallen by the wayside."Deutsch DG. A Personal Retrospective: Elevating Anandamide (AEA) by Targeting Fatty Acid Amide Hydrolase (FAAH) and the Fatty Acid Binding Proteins (FABPs). Frontiers in Pharmacology. 2016;7:370. doi:10.3389/fphar.2016.00370. To date a transmembrane protein transporter has not been identified.

References

{{Cannabinoidergics *Trans Neurochemistry

See also

References