Cortistatin: a natural somatostatin analog.

Cortistatin (CST) is a recently discovered neuropeptide from the somatostatin gene family named after its predominantly cortical expression and ability to depress cortical activity. CST shows many remarkable structural and functional similarities to its related neuropeptide somatostatin. However, the many physiological differences between CST and somatostatin are just as remarkable as the similarities. CST-14 shares 11 of its 14 amino acids with somatostatin-14, including the FWKT tetramer thought to be responsible for somatostatin's receptor interactions and the pair of cysteine residues that likely render the peptides cyclic. Yet the nucleotide sequences and chromosomal localizations of these genes clearly indicate they are products of separate genes and CST's activity in the brain is widely distinct from that of somatostatin. Now cloned from human, mouse and rat sources, in vitro assays show that CST is able to bind all five cloned somatostatin receptors and shares many pharmacological and functional properties with somatostatin, including the depression of neuronal activity and inhibition of GH release. However, distinct from somatostatin, CST has been shown to induce slow-wave sleep, reduce locomotor activity, and activate cation selective currents not responsive to, or antagonized by, somatostatin. Here we address the discovery and characterization of this novel somatostatin-like neuropeptide, including its cloning, expression and pharmacology. We also examine the evidence pointing towards a specific receptor for this novel neuropeptide member of the somatostatin gene family.