Full-length reviewCortistatin: a member of the somatostatin neuropeptide family with distinct physiological functions
Section snippets
Cloning, chromosomal mapping and structure of the cortistatin gene
The cDNA encoding cortistatin was isolated through characterization of regional specific rat brain mRNAs using directional tag PCR subtractive hybridization by de Lecea et al. in 1996 [19]. The sequence indicated the clone to be a novel 112 amino acid protein with a striking homology to somatostatin at its distal C-terminal end. The C-terminal 14 predicted amino acids, which are preceded by a pair of lysines, potentially forming a site for proteolytic cleavage, share 11 residue identities with
Cortistatin regulatory elements
Analysis of the regulatory elements for the preprocortistatin gene, recently determined by Calbet et al. [9], indicates that the regulatory elements of preprocortistatin and preprosomatostatin genes share few similarities (<30% using the BESTFIT program). The preprocortistatin transcriptional regulatory region lacks a TATA box or Initiator element and is GC rich in the proximal region. The promoter region contains a GATA motif at the −107 position which raises the possibility of basal
Regulation of cortistatin mRNA expression
The pattern of accumulation of cortistatin mRNA during development was examined using Northern blot and in situ hybridization. The 600 nucleotide band corresponding to preprocortistatin was observed in rats initially between P5 and P10, achieving maximal levels by P15, and subsequently reducing slightly in intensity into adulthood [20]. By in situ hybridization preprocortistatin mRNA was detected in the cortical plate, subiculum and stratum oriens of the hippocampus starting at P0. By P5 the
Localization of cortistatin
Using the technique of in situ hybridization, cortistatin mRNA has been shown to be essentially restricted in its expression to the cortex and hippocampus (Fig. 4A). This is in contrast to the expression of its relative somatostatin which is widely expressed in central and peripheral tissues [59], [71]. The brain specific nature of cortistatin expression was originally indicated by Northern blot: cortistatin mRNA was found in rat brain but not in adrenal gland, liver, spleen, thymus, ovary,
Structure of the cortistatin peptide
The putative 112 amino acid protein encoded by the preprocortistatin gene contains multiple sites at which endoproteolysis may occur. Recently Puebla et al. [65] have shown that preprocortistatin is indeed cleaved at the two C-terminal dibasic cleavage sites, KK and KR, to produce rCST14 and rCST29 analogously to SST14 and SST28. However, evidence of cleavage at both C-terminal dibasic sites to produce rCST14 and rCST13 was not found. The ratio of rCST14:rCST29:preprocortistatin in tissue
Cortistatin pharmacology
Given the apparent structural homologies between cortistatin and somatostatin the first target receptors tested for CST14 binding were the somatostatin receptors. Somatostatin binds to five different known receptors, named SSTR1-5, which are members of the 7-transmembrane G-protein coupled receptor superfamily. The receptors are widely distributed in the brain, and periphery, with distinct patterns of expression [38], [59], [71]. SSTRs transduce ligand-binding into cellular effects via G
Cortistatin electrophysiology
The first observation of the electrophysiological effects of cortistatin was superfusion of rCST14 on the hippocampal slice preparation [19]. The rCST14 hyperpolarized current- and voltage-clamped hippocampal neurons as evinced by inhibition of action potential firing, in a similar manner to SST14. The effect of rCST29 on the same preparation was indistinguishable from that of rCST14 (de Lecea, unpublished data). As a means to explain the mechanism of cortistatin-induced inhibition, the effect
Behavioral and neurobiological effects of cortistatin
Cortistatin was originally shown to have sleep promoting properties and effects on animal locomotor behavior. Infusion of up to 6 nmol rCST14 into rat brain ventricles induced hypoactivity in the treated rat population. The EEG for rCST14 treated animals showed a significant increase in cortical slow waves (1–4 Hz), and polygraphic recording indicated that the rCST14 injected animals spent significantly more time in slow wave sleep and less time in paradoxical (REM) sleep than control injected
Sleep promoting properties
The observation that cortistatin is mainly expressed in the cortex, and in particular, in local circuit inhibitory neurons, led to the hypothesis that the endogenous peptide may have a role in modulating cortical activity. Indeed, ICV injection of nanomolar amounts of CST14 significantly increased the number and duration of slow-wave sleep episodes both in normal and reversed light/dark cycles.
How does cortistatin promote sleep? Initial experiments have shown that application of CST14
Cortistatin and neuroprotection
Cortistatin has also been demonstrated to be neuroprotective against kainate-induced neurotoxicity in rat brains. Injection of the excitotoxic seizure inducing compound kainic acid (KA) caused seizure behavior in injected rats, which could be significantly reduced by prior ICV injection of rCST14. KA also caused significant neuronal death in the CA1 and CA3 regions of the hippocampus, an effect that could be blocked by application of rCST14 [7]. The neuroprotective properties of cortistatin are
Cortistatin in the somatostatin-like Cys–Cys loop family of peptides
Cortistatin shares many structural and functional properties with somatostatin. The amino acid sequences of the bioactive peptides, gene structures, partial coexpression, activation of common receptors and signaling pathways, and inhibition of neurons via activation of the M-current all indicate a duplication of function between these two peptides. Indeed the lack of a significant phenotype in mice lacking the gene for somatostatin [36] suggests that cortistatin at least partly duplicates
Does cortistatin have a specific receptor?
It is clear that cortistatin is capable of activating all known somatostatin receptors. However, it has not yet been shown that the observed in vitro or artificially induced activation of somatostatin receptors reflects in vivo events. Additionally, a large body of experimental evidence, discussed above, actually points towards the in vivo effects of cortistatin being mediated by receptors which are distinct from the classically defined somatostatin receptors. In summary this evidence includes:
Acknowledgements
This work was supported in part by grants from NIH (MH58543 and AG17354) to LdL. ADS is a NRSA fellow.
References (87)
- et al.
The interaction of GATA-binding proteins and basal transcription factors with GATA box-containing core promoters. A model of tissue-specific gene expression
J. Biol. Chem.
(1994) - et al.
Behavioral changes following central injection of cysteamine in rats
Brain Res.
(1986) - et al.
Protective effects of cortistatin (CST-14) against kainate-induced neurotoxicity in rat brain
Brain Res.
(1998) - et al.
Molecular basis of myotonic dystrophy: expansion of a trinucleotide (CTG) repeat at the 3′ end of a transcript encoding a protein kinase family member [published erratum appears in Cell 1992 Apr 17;69(2):385]
Cell
(1992) - et al.
Cortistatin and somatostatin mRNAs are differentially regulated in response to kainate
Brain Res. Mol. Brain Res.
(1999) - et al.
Somatostatin- and urotensin II-related peptides: molecular diversity and evolutionary perspectives
Regul. Pept.
(1997) Intracerebroventricular infusion of somatostatin selectively increases paradoxical sleep in rats
Brain Res.
(1986)- et al.
Multiple genes for neuropeptides and their receptors: co-evolution and physiology
Trends Neurosci.
(1999) - et al.
cDNA cloning, mRNA distribution and chromosomal mapping of mouse and human preprocortistatin
Genomics
(1997) - et al.
Thalamic and thalamocortical mechanisms underlying 3 Hz spike-and-wave discharges
Prog. Brain Res.
(1999)