Structure-function relationships of galanin

Synthetic galanin fragments and analogues provide tools that can be exploited to investigate the molecular basis of the physiologic action of galanin (Tatemoto et al., 1983), as well as for the production of region-specific antibodies (Yanaihara et al., 1989). We have previously reported that synthetic porcine galanin (10−9∼10−7M) caused a significant suppression of glucose (300 mg%)-induced insulin release from the isolated perfused rat pancreas (Takeda et al., 1987). Subsequent structure-function studies using synthetic porcine galanin fragments indicate that removal of the amino-terminal residue, Gly, caused a complete loss of the inhibitory action, and a further shortening of the peptide chain gave peptides having insulinotropic effects, the maximum potency occurred at the 15∼29 sequence (Yanaihara et al., 1988b). This is the first demonstration of a neuropeptide and its fragments that possess opposite effects in action on a single biological system (i.e., insulin release). These results suggest strongly that the second residue from the amino-terminal, Trp, is integral in this reversal of the inhibitory action of galanin. Based on these observations, substitution of the Trp residue with D-Trp, Phe or Ala was carried out. The modified peptides, [D-Trp2]porcine galanin and [Phe2]porcine galanin, did not cause a significant change in the galanin effect on glucose-induced insulin release, whereas [Ala2]porcine galanin was found to have an enhancement effect on insulin release, similar to that seen with shorter galanin fragments (Yanaihara et al., 1988a,b). Based on the secondary structures of the analogs and fragments, as predicted by the Chou-Fasman method (Chou and Fasman, 1974a,b), a high incidence of β-sheet structure in the amino-terminal region of galanin (figure 1) was indicated to be essential for the inhibitory effect of galanin on glucose-induced insulin release.