CART (55-102) (RAT)

Structure

CART peptides of different lengths have been found in various tissues. The rat central nervous system contains CART55–102 and CART62–102 fragments. In the periphery, longer products are generated in addition to CART55–102. Adrenal glands in the rat produce two peptides, CART1–89 and CART10–89. The most widely studied peptides are CART55–102 and CART62–102 . Both peptides contain a cysteine-knot motif, which is critical for the biological activity of the hormone. The human CART42–89 corresponds to the rodent CART55–102. Genome studies have revealed that fish have multiple CART genes. Two different goldfish CART55–102 (Goldfish I and II) genes present high homology with their mammalian counterparts in their C-terminal end region.

Gene, mRNA, and precursor

The human CART gene, CARTPT, located in the 5q13.2 region, consists of two introns and three exons. Due to alternative splicing, the rodent CART mRNA produces two spliced variants of proCART. Long and short forms encode a 102 aa sequence or an 89 aa sequence, respectively. Only the latter has been found in humans.

Synthesis and release

In hypothalamic explants, the neuropeptide Y (NPY) significantly increased the release of CART (55–102) immunoreactivity. In vivo experiments showed that leptin administration induces Fos expression in hypothalamic CART neurons. NPY and CART are coexpressed in the same neurons in the dorsomedial hypothalamus in chronic obesity. These neurons are activated by peripheral leptin treatment in diet-induced obesity. Thus, CART peptides are anorexigenic and closely associated with leptin and NPY, two important food intake regulators. CART is also released in response to repeated dopamine release in the nucleus accumbens.

Receptors

Although CART-responsive cell lines or neurons were reported, the receptor for CART has not been clarified yet. It is speculated that CART55–102 and CART62–102 do not share the same receptor, as they show different physiological activities in vivo. In 2020, CART55-102 was suggested to be a ligand of an orphan GPCR, GPR160, from biological assays. Further pharmacology would be required on GPR160 and CART for confirmation. The signal transduction pathway is predicted to be mainly coupled to the Gi/o protein and to stimulate ERK1/2 activation or inhibit calcium signaling.

Biological functions

In the goldfish, the central administration of human CART has been shown to decrease food intake. In mammals, CART modulates various physiological processes such as feeding, energy expenditure, stress control, and endocrine secretion.

Clinical implications

In an obese 10-year-old boy, where the onset of obesity was at the age of 2, a G-to-C transversion at nucleotide 729 of the CART gene was identified, resulting in missense mutation, a leucine to phenylalanine substitution at codon 34 (L34F). This mutation affects posttranslational processing and causes bioactive CART deficiency in the serum. The L34F mutation segregated with severe obesity over three generations in this family, and was not identified in the control population. The affected subjects demonstrated reduced resting energy expenditures. Further, sequence variability in the CART gene has been identified as being related to obesity in several hundred French subjects.

General Description

CART, so named because of upregulation by cocaine and amphetamine, is thought to be involved in the regulation of feeding and stress. However, its cognate receptor has not yet been identified. In the 1980s, a fragment of the CART peptide was identified in an extract of ovine hypothalamus. Fifteen years later, the level of CART mRNA was found to increase in the rat striatum after acute administration of cocaine and amphetamine. Subsequently, in 1999, CART peptides were extracted and sequenced from the rat, and it was found that two different forms (CART55–102 and CART62–102) were present.

storage

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