Abstract
In most serpentine type receptors the third intracellular loop (ICL-3) is responsible for the interaction with heterotrimeric G proteins and for transduction of a 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, consequently, may be considered as prototypes for the development of selective regulators of these systems. We have originally synthesized peptides corresponding to the 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 G i 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. The peptide 255–269 of Som1R decreased the regulatory effects of somatostatin and the selective Som1R agonist, CH-275, realized via the homologous receptor, while the peptide 240–254 of Som2R, on the contrary, increased the AC inhibitory effect of CH-275. Both peptides insignificantly influenced regulatory effects of the Som2R agonist octreotide. Thus, the peptides studied by us are selective regulators of the somatostatin-sensitive AC system. Using the peptides we have demonstrated that ICL-3 of both Som1R and Som2R includes the main molecular determinants that are responsible for activation of G i proteins and regulation of the AC system by somatostatin and its analogues.
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Abbreviations
- AC:
-
Adenylyl cyclase
- ACS:
-
Adenylyl cyclase system, G s and G i -stimulatory or inhibitory heterotrimeric G protein, respectively
- ICL-3:
-
C-terminal region of the third intracellular loop
- Som1R and Som2R-somatostatin receptors of the types 1 and 2, respectively, 5-HTR:
-
5-hydroxytryptamine receptor
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Original Russian Text © A.O. Shpakov, E.A. Shpakova, 2011, published in Biomeditsinskaya Khimiya.
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Shpakov, A.O., Shpakova, E.A. Development of non-hormonal regulators of the adenylyl cyclase signaling system based on the peptides, derivatives of the third intracellular loop of somatostatin receptors. Biochem. Moscow Suppl. Ser. B 5, 246–252 (2011). https://doi.org/10.1134/S1990750811030127
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DOI: https://doi.org/10.1134/S1990750811030127