Invited review
CART peptides

https://doi.org/10.1016/S0167-0115(00)00096-3Get rights and content

Abstract

CART peptides are among the newest putative peptide neurotransmitter/cotransmitters. They show no significant homology to any other peptide, and they are thought to have a role in reward and reinforcement, feeding, development, sensory processing, stress and endocrine control.

Introduction

CART peptides are among the most recently discovered putative peptide neurotransmitters, and are thought to be involved in feeding, reward and reinforcement, development, sensory processing, endocrine regulation and stress [1]. The name CART refers to the mRNA discovered by Douglass et al. [2] and is an acronym for cocaine and amphetamine regulated transcript. To avoid ambiguity, this paper will explicitly refer to either the mRNA or the peptide; the amino acid sequences of CART proteins from various species are shown in Fig. 1. The first CART peptide fragment was identified nearly 2 decades ago in extracts of sheep hypothalamus and was partially sequenced [3], but its significance was unknown at the time. In 1995, Douglass et al. [2] described CART mRNA as one that increased in rat striatum after acute administrations of cocaine or amphetamine, and part of the rat CART mRNA sequence corresponded to that of the ‘unknown’ ovine peptide found by Spiess et al. [3] More recently, at least six CART proteins/peptides have been identified in rodent and human and some have been purified and sequenced (Fig. 2, Fig. 3) [4], [5]. The gene for CART peptides has been characterized in both human [6] and mouse [7].

Section snippets

CART mRNA and peptides

The identification of CART mRNA by Douglass et al. [2] allowed for the prediction of the amino acid sequence of the protein product. It was clear that CART protein (Fig. 1) had a predicted leader sequence of 27 amino acids, suggesting that it was destined for the secretory pathway. It also had pairs of basic amino acids indicating a likelihood of processing by cleavage. This protein structure was highly reminiscent of many known and well-characterized peptide neurotransmitter precursors [8].

Anatomical localization

A detailed description of the anatomy of CART-containing neurons [11], [12], [13], [14], [15], [16], [17], [18], [19], [20], [21], [22] is beyond the scope of this paper, but some highlights follow. Studies of the distribution of CART mRNA by Northern analysis and by in situ hybridization [2], [20], [21], and of the localization of CART peptides by immunocytochemistry and RIA [11], [12], [13], [14], [15], [16], [17], [18], [19], [21], [22], clearly indicated that the CART system is not

CART peptides and feeding

As mentioned above, CART peptides are found in neurons associated with feeding. Injection of CART peptides into the brain ventricular system of the rat causes a rapid inhibition of feeding [28], [29], [30], [31], [32]. The most potent of these peptides, and one that occurs endogenously, is rlCART 55–102 (See Fig. 1), but rlCART 62–102 also has similar activity [32]. Smaller peptides have been reported to be active [29], but this has been challenged [21]. Also, larger peptides (rsCART 10–89) are

Neurotrophic actions

A patent publication by Amgen [34] indicates that rsCART 1–89 and rlCART 1–102 have neurotrophic properties. For example, at a concentration of 0.01 ng/ml, rsCART 1–89 increased the survival of motorneurons and enhanced the number of dopamine transporters in primary cell cultures. In addition to having neurotrophic effects in vitro, CART peptides are in fact found in mammals during development, as evidenced by their direct identification by Western blotting [7]. Moreover, several ESTs have been

Other effects of CART peptides

CART peptides are found in anatomical areas associated with sensory transmission and processing. These areas include the dorsal horns of the spinal cord, a subpopulation of ganglion cells in the retina, some nodose and dorsal root ganglion cells, mitral cells in the olfactory bulb, somatosensory barrels and other regions [1]. The precise role of CART in these neurons remains to be determined.

CART peptides appear to be involved in stress and endocrine function. The peptides are found in several

CART receptors

It is clear that CART peptides are found in the brain, share many aspects with accepted peptide neurotransmitters [8], and have effects when administered to animals. However, there are no reports of the identification of CART receptors by binding or by cloning. Injection of CART peptide into the brain does cause an elevation of cfos in groups of neurons that contain CART peptides [24], [37], [38]. However, with the availability of active CART peptides, achieving receptor binding seems to be

References (38)

  • J. Douglass et al.

    PCR differential display identifies a rat brain mRNA that is transcriptionally regulated by cocaine and amphetamine

    J. Neurosci.

    (1995)
  • J. Spiess et al.

    Isolation and sequence analysis of a somatostatin-like polypeptide from ovine hypothalamus

    Biochemistry

    (1981)
  • M.J. Kuhar et al.

    CART peptide analysis by Western blotting

    Synapse

    (1999)
  • L. Thim et al.

    Tissue-specific processing of cocaine- and amphetamine-regulated transcript peptides in the rat

    Proc. Natl. Acad. Sci.

    (1999)
  • F. Strand

    Neuropeptides: regulators of physiological processes

    (1999)
  • K.M. Gautvik et al.

    Overview of the most prevalent hypothalamus-specific mRNAs, as identified by directional tag PCR subtraction

    Proc Natl Acad Sci USA

    (1996)
  • Hastrup S, Christiansen K, Thim L, Judge M, Kristensen, P. Novo Nordisk. Polypeptide with appetite regulating activity....
  • E.O. Koylu et al.

    Immunohistochemical localization of novel CART peptides in rat hypothalamus, pituitary and adrenal gland

    J. Neuroendocrinol.

    (1997)
  • E.O. Koylu et al.

    CART peptide immunohistochemical localization in the rat brain

    J. Comp. Neurol.

    (1998)
  • Cited by (113)

    • Differences in the dopaminergic reward system in rats that passively and actively behave in the Porsolt test

      2019, Behavioural Brain Research
      Citation Excerpt :

      Furthermore, stress exposure may influence mesolimbic neurotransmission resulting in changes in response to psychoactive substances, an increased vulnerability to addiction and a stronger propensity to develop affective disorders [9,22,23]. One of the factor involved in the regulation of dopamine signaling is endogenous CART (Cocaine- and Amphetamine-Regulated Transcript) peptide [24], expressed in many regions of mesolimbic system (nucleus accumbens, ventral tegmental area, amygdala) and hypothalamus [25–28]. CART is thought to participate in multiple processes in the central nervous system including stress response, anxiety, depression, reward and addiction likely via attenuation of dopaminergic neurotransmission [24,26,29–32].

    • Intestinal CART is a regulator of GIP and GLP-1 secretion and expression

      2018, Molecular and Cellular Endocrinology
      Citation Excerpt :

      Both major CART forms have been shown to be biologically active, however activity differences were also reported (reviewed in (Dylag et al., 2006)). CART expression has been demonstrated in the central, peripheral and enteric nervous systems (Ekblad et al., 2003; Kristensen et al., 1998; Kuhar et al., 2000), in adipose tissue (Banke et al., 2013), as well as in endocrine cells in the pancreatic islets (Wierup and Sundler, 2006; Wierup et al., 2004a), the thyroid (Wierup et al., 2007) and the adrenal medulla (Wierup et al., 2007; Koylu et al., 1997). CART has been demonstrated in blood (Bech et al., 2008; Ramachandran et al., 2015; Vicentic et al., 2004; Yilmaz et al., 2014), however information on the regulation of CART secretion and about the main sources of circulating CART is limited (Rogge et al., 2008; Bech et al., 2008; Vicentic et al., 2004).

    View all citing articles on Scopus
    1

    Georgia Research Alliance Eminent Scholar and Candler Professor.

    View full text