Cocaine- and amphetamine-regulated transcript, also known as CART, is a
neuropeptide protein
Proteins are large biomolecules and macromolecules that comprise one or more long chains of amino acid residues. Proteins perform a vast array of functions within organisms, including catalysing metabolic reactions, DNA replication, res ...
that in humans is encoded by the ''CARTPT''
gene
In biology, the word gene (from , ; "... Wilhelm Johannsen coined the word gene to describe the Mendelian units of heredity..." meaning ''generation'' or ''birth'' or ''gender'') can have several different meanings. The Mendelian gene is a b ...
.
CART appears to have roles in reward, feeding, and stress, and it has the functional properties of an endogenous
psychostimulant.
Function
CART is a
neuropeptide that produces similar behavior in animals as
cocaine
Cocaine (from , from , ultimately from Quechua: ''kúka'') is a central nervous system (CNS) stimulant mainly used recreationally for its euphoric effects. It is primarily obtained from the leaves of two Coca species native to South Ameri ...
and
amphetamine, but conversely blocks the effects of cocaine when they are co-administered. The peptide is found in several areas, among them the
ventral tegmental area (VTA) of the brain. When CART was injected into rat VTA, increased
locomotor activity was seen, which is one of the signs of "central stimulation" caused by psychostimulants, such as cocaine and amphetamine. The same rats also tended to return to the place where they were injected. This is called
conditioned place preference and is also seen after injection of cocaine.
CART peptides, in particular, CART(55–102), seem to have an important function in the regulation of energy homeostasis, and interact with several
hypothalamic appetite circuits. CART expression is regulated by several peripheral
peptide hormone
Peptide hormones or protein hormones are hormones whose molecules are peptide, or proteins, respectively. The latter have longer amino acid chain lengths than the former. These hormones have an effect on the endocrine system of animals, including h ...
s involved in appetite regulation, including
leptin,
cholecystokinin
Cholecystokinin (CCK or CCK-PZ; from Greek ''chole'', "bile"; ''cysto'', "sac"; ''kinin'', "move"; hence, ''move the bile-sac (gallbladder)'') is a peptide hormone of the gastrointestinal system responsible for stimulating the digestion of fat an ...
and
ghrelin
Ghrelin (; or lenomorelin, INN) is a hormone produced by enteroendocrine cells of the gastrointestinal tract, especially the stomach, and is often called a "hunger hormone" because it increases the drive to eat. Blood levels of ghrelin are hi ...
,
with CART and cholecystokinin having synergistic effects on appetite regulation.
CART is released in response to repeated dopamine release in the nucleus accumbens, and may regulate the activity of neurons in this area.
CART production is upregulated by
CREB
CREB-TF (CREB, cAMP response element-binding protein) is a cellular transcription factor. It binds to certain DNA sequences called cAMP response elements (CRE), thereby increasing or decreasing the transcription of the genes. CREB was first de ...
,
a protein thought to be involved with the development of drug addiction, and CART may be an important therapeutic target in the treatment of stimulant abuse.
Tissue distribution
CART is an
anorectic
An anorectic or anorexic is a drug which reduces appetite, resulting in lower food consumption, leading to weight loss. By contrast, an appetite stimulant is referred to as orexigenic.
The term is (from the Greek ''ἀν-'' (an-) = "without" a ...
peptide and is widely expressed in both the central and peripheral nervous systems, particularly concentrated in the
hypothalamus
The hypothalamus () is a part of the brain that contains a number of small nuclei with a variety of functions. One of the most important functions is to link the nervous system to the endocrine system via the pituitary gland. The hypothalamu ...
.
CART is also expressed outside of the nervous system in
pituitary
In vertebrate anatomy, the pituitary gland, or hypophysis, is an endocrine gland, about the size of a chickpea and weighing, on average, in humans. It is a protrusion off the bottom of the hypothalamus at the base of the brain. The hypoph ...
endocrine cells,
adrenomedullary cells, islet
somatostatin cells, and in rat antral
gastrin cells.
Other structures and pathways associated with CART expression include the
mesolimbic pathway
The mesolimbic pathway, sometimes referred to as the reward pathway, is a dopaminergic pathway in the brain. The pathway connects the ventral tegmentum, ventral tegmental area in the midbrain to the ventral striatum of the basal ganglia in the for ...
(linking the
ventral tegmental area to the
nucleus accumbens
The nucleus accumbens (NAc or NAcc; also known as the accumbens nucleus, or formerly as the ''nucleus accumbens septi'', Latin for " nucleus adjacent to the septum") is a region in the basal forebrain rostral to the preoptic area of the hypot ...
) and
amygdala
The amygdala (; plural: amygdalae or amygdalas; also '; Latin from Greek, , ', 'almond', 'tonsil') is one of two almond-shaped clusters of nuclei located deep and medially within the temporal lobes of the brain's cerebrum in complex verte ...
.
CART is also found in a subset of
retinal ganglion cells (RGCs), the primary afferent neurons in the retina. Specifically, it labels ON/OFF Direction Selective Ganglion Cells (ooDSGCs), a subpopulation of RGCs that stratify in both the ON and OFF sublamina of the Inner Plexiform Layer (IPL) of the retina. It is also found in a subset of amacrine cells in the Inner Nuclear Layer. No role as of yet has been proposed for the peculiar location of this protein in these cell types.
Clinical significance
Studies of CART(54–102) action in rat
lateral ventricle
The lateral ventricles are the two largest ventricles of the brain and contain cerebrospinal fluid (CSF). Each cerebral hemisphere contains a lateral ventricle, known as the left or right ventricle, respectively.
Each lateral ventricle resemble ...
and
amygdala
The amygdala (; plural: amygdalae or amygdalas; also '; Latin from Greek, , ', 'almond', 'tonsil') is one of two almond-shaped clusters of nuclei located deep and medially within the temporal lobes of the brain's cerebrum in complex verte ...
suggest that CART plays a role in anxiety-like behavior, induced by
ethanol withdrawal in rats.
Studies on CART
knock-out mice indicates that CART modulates the locomotor, conditioned place preference and cocaine
self-administration effects of
psychostimulants
Stimulants (also often referred to as psychostimulants or colloquially as uppers) is an overarching term that covers many drugs including those that increase activity of the central nervous system and the body, drugs that are pleasurable and inv ...
. This suggests a positive neuromodulatory action of CART on the effects of psychostimulants in rats.
CART is altered in the ventral tegmental area of cocaine overdose victims, and a mutation in the CART gene is associated with alcoholism.
By inhibiting the rewarding effects of cocaine, CART has a potential use in treating cocaine addiction.
CART peptides are inhibitors of food intake (anorectic) and closely associated with
leptin and
neuropeptide Y, two important food intake regulators. CART hypoactivity in the hypothalamus of depressed animals is associated with hyperphagia and weight gain.
CART is thought to play a key role in the opioid mesolimbic dopamine circuit that modulates natural reward processes. CART also appears to play an important role in higher brain functions like
cognition.
History
CART was found by examining changes in the brain following cocaine or amphetamine administration. CART
mRNA
In molecular biology, messenger ribonucleic acid (mRNA) is a single-stranded molecule of RNA that corresponds to the genetic sequence of a gene, and is read by a ribosome in the process of synthesizing a protein.
mRNA is created during the ...
increased with cocaine administration. One of the goals was to find an
endogenous anoretic substance. CART inhibited rat food intake by as much as 30 percent. When naturally occurring CART peptides were blocked by means of injecting antibodies for CART, feeding was increased. This led to suggestions that CART may play a role – though not being the only peptide – in satiety. In the late 1980s, researchers started to synthesize structurally cocaine-like and functionally CART-like substances in order to find medications that could help treat eating disorders as well as cocaine abuse. Chemically, these substances belong to
phenyltropane
Phenyltropanes (PTs) were originally developed to reduce cocaine addiction and dependency. In general these compounds act as inhibitors of the plasmalemmal monoamine reuptake transporters. Although RTI holds a strong position in this field, ...
s.
CART receptor
The putative receptor target for CART evaded identification through 2011,
however ''in vitro'' studies strongly suggested that CART binds to a specific
G protein-coupled receptor
G protein-coupled receptors (GPCRs), also known as seven-(pass)-transmembrane domain receptors, 7TM receptors, heptahelical receptors, serpentine receptors, and G protein-linked receptors (GPLR), form a large group of evolutionarily-related p ...
coupled to Gi/Go, resulting in increased
ERK release inside the cell.
In 2020, CART was identified as the ligand for GPCR160.
Several fragments of CART have been tested to try and uncover the
pharmacophore
300px, An example of a pharmacophore model.
A pharmacophore is an abstract description of molecular features that are necessary for molecular recognition of a ligand by a biological macromolecule. IUPAC defines a pharmacophore to be "an ensemble o ...
,
but the natural splicing products CART(55–102) and CART(62–102) are still of highest activity, with the reduced activity of smaller fragments thought to indicate that a compact structure retaining all three of CART's disulphide bonds is preferred.
See also
*
Amphetamine
*
Cocaine
Cocaine (from , from , ultimately from Quechua: ''kúka'') is a central nervous system (CNS) stimulant mainly used recreationally for its euphoric effects. It is primarily obtained from the leaves of two Coca species native to South Ameri ...
References
External links
*
{{Neuropeptides
Amphetamine