Abstract: In the majority of the serpentine type receptors the third intracellular loop (ICL-3) is responsible for interaction with heterotrimeric G-proteins and for transduction of hormonal signal to the enzymes, generators of the second messengers. It was found that the peptides corresponding to ICL-3 influence functional activity of hormonal signaling systems in the absence of the hormone and, in consequence, can be considered as prototypes for the development of selective regulators of these systems. We have originally synthesized peptides corresponding to C-terminal regions 255-269 and 240-254 of ICL-3 of type 1 and 2 rat somatostatin receptors (Som1R and Som2R). Micromolar concentrations of these peptides activated Gi-proteins and inhibited forskolin-stimulated activity of adenylyl cyclase (AC) in rat brain tissues. The peptide 255-269 of Som1R is a selective antagonist of Som1R, and the peptide 240-254 of Som2R is an agonist of Som1R. So, the peptide 255-269 of Som1R decreased the regulatory effects of somatostatin and selective Som1R-agonist CH-275 realized via the receptor homologous to them, while the peptide 240-254 of Som2R, on the contrary, increased AC inhibitory action of CH-275. Both peptides insignificantly influenced regulatory effects of the Som2R-agonist octreotide. Summing up, the peptides studied by us are selective regulators of somatostatin-sensitive AC system. Using the peptides it was shown that ICL-3 of Som1R and Som2R includes the main molecular determinants that are responsible for activation of Gi-proteins and regulation of AC system by somatostatin and its analogues.
Reference: Shpakov A.O., Shpakova E.A., Development of non-hormonal regulators of adenylyl cyclase signaling system on the basis of peptides, derivatives of the third intracellular loop of somatostatin receptors, Biomeditsinskaya khimiya, 2012, vol: