Cocaine- and amphetamine-regulated transcript
Encyclopedia
Cocaine and amphetamine regulated transcript also known as CART is a protein
that in humans is encoded by the CARTPT gene
. CART appears to have roles in reward, feeding, and stress, and it has the functional properties of an endogenous psychostimulant.
that also serves as a neurotransmitter
. It produces similar behaviour in animals to cocaine
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 is injected into rat VTA, increased locomotor
activity is seen, which is one of the signs of "central stimulation" caused by substances such as cocaine and amphetamine. The rats also tended to return to the place where they had been injected. This is called conditioned place preference
and is seen after injection of cocaine. CART is found at the same locations where cocaine and methamphetamine
mainly act in the brain. This has led to speculation that CART could be an "endogenous cocaine".
CART peptides, in particular, CART (55–102), seem to have an important function in the regulation of energy homeostasis, and interact with several central appetite circuits. CART expression is regulated by several peripheral peptide hormone
s involved in appetite regulation, including leptin
, cholecystokinin
and ghrelin
, 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
, 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.
. CART is outside of the nervous system also expressed in pituitary endocrine cells, adrenomedullary cells, islet somatostatin
cells, and in rat antral gastrin
cells.
suggest that CART play 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
effect of psychostimulants. This suggests a positive neuromodulatory action of CART on psychostimulants effect on rat. CART is altered in the ventral tegmental area of cocaine overdose victims, and a mutation in the CART gene associates with alcoholism. CART peptides are inhibitors of food intake (anorexigenic) and closely associated with leptin
and neuropeptide Y
, two important food intake regulators. CART peptides are also involved in fear
and startle behavior.
anorexigenic substance. CART inhibited rat food intake by as much as 30 percent. When naturally-occurring CART peptides were blocked by means of injecting antibodies to CART, feeding increased. This led to suggestions CART may play a role - though not being the only peptide - in satiety. In the end of 1980s, researchers started to synthesize cocaine-like and CART-like-acting substances in order to find medications that could affect eating disorders as well as cocaine abuse. These cocaine-like substances are called phenyltropane
s.
coupled to Gi/Go, resulting in increased ERK
release inside the cell.
Several fragments of CART have been tested to try and uncover the pharmacophore
, 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.
Protein
Proteins are biochemical compounds consisting of one or more polypeptides typically folded into a globular or fibrous form, facilitating a biological function. A polypeptide is a single linear polymer chain of amino acids bonded together by peptide bonds between the carboxyl and amino groups of...
that in humans is encoded by the CARTPT gene
Gene
A gene is a molecular unit of heredity of a living organism. It is a name given to some stretches of DNA and RNA that code for a type of protein or for an RNA chain that has a function in the organism. Living beings depend on genes, as they specify all proteins and functional RNA chains...
. CART appears to have roles in reward, feeding, and stress, and it has the functional properties of an endogenous psychostimulant.
Function
CART is a neuropeptideNeuropeptide
Neuropeptides are small protein-like molecules used by neurons to communicate with each other. They are neuronal signaling molecules, influence the activity of the brain in specific ways and are thus involved in particular brain functions, like analgesia, reward, food intake, learning and...
that also serves as a neurotransmitter
Neurotransmitter
Neurotransmitters are endogenous chemicals that transmit signals from a neuron to a target cell across a synapse. Neurotransmitters are packaged into synaptic vesicles clustered beneath the membrane on the presynaptic side of a synapse, and are released into the synaptic cleft, where they bind to...
. It produces similar behaviour in animals to cocaine
Cocaine
Cocaine is a crystalline tropane alkaloid that is obtained from the leaves of the coca plant. The name comes from "coca" in addition to the alkaloid suffix -ine, forming cocaine. It is a stimulant of the central nervous system, an appetite suppressant, and a topical anesthetic...
and amphetamine
Amphetamine
Amphetamine or amfetamine is a psychostimulant drug of the phenethylamine class which produces increased wakefulness and focus in association with decreased fatigue and appetite.Brand names of medications that contain, or metabolize into, amphetamine include Adderall, Dexedrine, Dextrostat,...
, 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 is injected into rat VTA, increased locomotor
Locomotor system
Locomotor system may mean:* Animal locomotion system* Human musculoskeletal system, also known simply as "the locomotor system"...
activity is seen, which is one of the signs of "central stimulation" caused by substances such as cocaine and amphetamine. The rats also tended to return to the place where they had been injected. This is called conditioned place preference
Conditioned place preference
Conditioned place preference is a technique commonly used in animal studies to evaluate preferences for environmental stimuli that have been associated with a positive or negative reward...
and is seen after injection of cocaine. CART is found at the same locations where cocaine and methamphetamine
Methamphetamine
Methamphetamine is a psychostimulant of the phenethylamine and amphetamine class of psychoactive drugs...
mainly act in the brain. This has led to speculation that CART could be an "endogenous cocaine".
CART peptides, in particular, CART (55–102), seem to have an important function in the regulation of energy homeostasis, and interact with several central appetite circuits. CART expression is regulated by several peripheral peptide hormone
Peptide hormone
Peptide hormones are a class of peptides that are secreted into the blood stream and have endocrine functions in living animals.Like other proteins, peptide hormones are synthesized in cells from amino acids according to an mRNA template, which is itself synthesized from a DNA template inside the...
s involved in appetite regulation, including leptin
Leptin
Leptin is a 16 kDa protein hormone that plays a key role in regulating energy intake and energy expenditure, including appetite and metabolism. It is one of the most important adipose derived hormones...
, cholecystokinin
Cholecystokinin
Cholecystokinin is a peptide hormone of the gastrointestinal system responsible for stimulating the digestion of fat and protein...
and ghrelin
Ghrelin
Ghrelin is a 28 amino acid peptide and hormone that is produced mainly by P/D1 cells lining the fundus of the human stomach and epsilon cells of the pancreas that stimulates hunger. Ghrelin levels increase before meals and decrease after meals. It is considered the counterpart of the hormone...
, 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
CREB is a cellular transcription factor. It binds to certain DNA sequences called cAMP response elements , thereby increasing or decreasing the transcription of the downstream genes....
, 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 anorexigenic peptide and is widely expressed in both the central and peripheral nervous systems, particularly concentrated in the hypothalamusHypothalamus
The Hypothalamus is a portion of the brain that contains a number of small nuclei with a variety of functions...
. CART is outside of the nervous system also expressed in pituitary endocrine cells, adrenomedullary cells, islet somatostatin
Somatostatin
Somatostatin is a peptide hormone that regulates the endocrine system and affects neurotransmission and cell proliferation via interaction with G-protein-coupled somatostatin receptors and inhibition of the release of numerous secondary hormones.Somatostatin...
cells, and in rat antral gastrin
Gastrin
In humans, gastrin is a peptide hormone that stimulates secretion of gastric acid by the parietal cells of the stomach and aids in gastric motility. It is released by G cells in the antrum of the stomach, duodenum, and the pancreas...
cells.
Clinical significance
Studies of CART (54–102) action in rat lateral ventricle and amygdalaAmygdala
The ' are almond-shaped groups of nuclei located deep within the medial temporal lobes of the brain in complex vertebrates, including humans. Shown in research to perform a primary role in the processing and memory of emotional reactions, the amygdalae are considered part of the limbic system.-...
suggest that CART play 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
Self-administration
Self-administration is, in its medical sense, the process of a subject administering a pharmacological substance to him-, her-, or itself. A clinical example of this is the subcutaneous "self-injection" of insulin by a diabetic patient....
effect of psychostimulants. This suggests a positive neuromodulatory action of CART on psychostimulants effect on rat. CART is altered in the ventral tegmental area of cocaine overdose victims, and a mutation in the CART gene associates with alcoholism. CART peptides are inhibitors of food intake (anorexigenic) and closely associated with leptin
Leptin
Leptin is a 16 kDa protein hormone that plays a key role in regulating energy intake and energy expenditure, including appetite and metabolism. It is one of the most important adipose derived hormones...
and neuropeptide Y
Neuropeptide Y
Neuropeptide Y is a 36-amino acid peptide neurotransmitter found in the brain and autonomic nervous system."NPY has been associated with a number of physiologic processes in the brain, including the regulation of energy balance, memory and learning, and epilepsy." The main effect is increased food...
, two important food intake regulators. CART peptides are also involved in fear
Fear
Fear is a distressing negative sensation induced by a perceived threat. It is a basic survival mechanism occurring in response to a specific stimulus, such as pain or the threat of danger...
and startle behavior.
History
CART was found by examining changes in the brain following cocaine or amphetamine administration. CART mRNA increased with cocaine administration. One of the goals was to find an endogenousEndogenous
Endogenous substances are those that originate from within an organism, tissue, or cell. Endogenous retroviruses are caused by ancient infections of germ cells in humans, mammals and other vertebrates...
anorexigenic substance. CART inhibited rat food intake by as much as 30 percent. When naturally-occurring CART peptides were blocked by means of injecting antibodies to CART, feeding increased. This led to suggestions CART may play a role - though not being the only peptide - in satiety. In the end of 1980s, researchers started to synthesize cocaine-like and CART-like-acting substances in order to find medications that could affect eating disorders as well as cocaine abuse. These cocaine-like substances are called phenyltropane
Phenyltropane
Phenyltropanes 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, they are not the only researchers that have prepared these...
s.
CART Receptor
The putative receptor target for CART has not yet been identified as of 2009, however in vitro studies strongly suggest that CART binds to a specific G protein-coupled receptorG protein-coupled receptor
G protein-coupled receptors , also known as seven-transmembrane domain receptors, 7TM receptors, heptahelical receptors, serpentine receptor, and G protein-linked receptors , comprise a large protein family of transmembrane receptors that sense molecules outside the cell and activate inside signal...
coupled to Gi/Go, resulting in increased ERK
Extracellular signal-regulated kinases
In molecular biology, extracellular-signal-regulated kinases or classical MAP kinases are widely expressed protein kinase intracellular signalling molecules that are involved in functions including the regulation of meiosis, mitosis, and postmitotic functions in differentiated cells...
release inside the cell.
Several fragments of CART have been tested to try and uncover the pharmacophore
Pharmacophore
thumb|right|300px|An example of a pharmacophore model.A pharmacophore is an abstract description of molecular features which are necessary for molecular recognition of a ligand by a biological macromolecule....
, 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.