Structural and compositional determinants of cortistatin activity

Cortistatin-14 (CST-14) is a putative novel neuropeptide that shares 11 of its 14 residues with somatostatin-14 (SRIF-14), Set its effects on sleep ph ysiology, locomotor behavior and hippocampal function are different from th ose of somatostatin, We studied the structural basis for cortistatin's dist inct biological activities. As with SRIF-14, CST-14 does not show any prefe rred conformation in solution, as determined by circular dichroism and nucl ear magnetic resonance. Synthetic cortistatin analogs were designed and syn thesized based on the cyclic structure of octreotide, Biological assays wer e carried out to determine their binding affinities to five somatostatin re ceptors (sst1-5) and their ability to produce changes in locomotor activity and to modulate hippocampal physiology and sleep. The results show that th e compound with N-terminal proline and C-terminal lysine amide exhibits cor tistatin-like biological activities, including reduction of population spik e amplitudes in the hippocampal CA1 region, decrease in locomotor activity and enhancement of slow-wave sleep 2, These findings suggest that both prol ine and lysine are necessary for cortistatin binding to its specific recept or. (C) 1999 Wiley-Liss, Inc.