Effects of polycationic peptides of different natures on the functional state of the serotonin-regulated adenylate cyclase system in the rat brain

Abstract

In animals of different phylogenetic levels, polycationic peptides are one of the most important regulators of the functional activities of hormonal signaling systems, including the adenylate cyclase signaling system (AC system). We compared the functional state of the AC system in the rat brain after treatment with three synthetic polycationic peptides (C-ɛAhx-YKAKKKKKKKWK (I), CK(C10)-ɛAhx-YKAKKKKKKKWK (II), and (NH2)64(K)32(K)16(K)8(K)4(K)2KA (III)) and the peptide toxin mastoparan, which do not have homology to signaling proteins, and the synthetic polycationic peptides ARERKATKTL255–264K (IV) and HSRKALKASL306–315K (V), which are derivatives of the C-terminal domains of the third cytoplasmic loop of the 1B and 6 serotonin receptors (SR). We found that the peptides I, II, and III stimulated heterotrimeric G-proteins of both the stimulating (Gs) and inhibiting (Gi) type, peptide IV and, mastoparan predominantly affected Gi-proteins, and peptide V mainly activated Gs-proteins. Peptides II and V stimulated basal AC activity, while mastoparan and peptides III and IV inhibited the forskolin-stimulated activity of the enzyme. The serotonin-induced stimulation of AC strongly decreased in the presence of peptide V, a derivative of SR of the sixth type coupled with Gs-proteins (the efficacy of the inhibitory effect of the peptides was V > II > III > IV ≅ mastoparan ≅ I). Inhibition of the AC system by serotonin decreased in the presence of peptide IV, a derivative of 1B SR coupled with Gi-proteins (the efficacy of inhibition was IV > III ≅ mastoparan > II ≥ I ≅ V). Inhibition of AC by the D2-agonist bromocriptine strongly decreased in the presence of mastoparan and peptide III, and peptide IV was less active (mastoparan ≥ III > IV > II > I ≅ V). Among the polycationic peptides studied peptides IV and V and SR derivatives caused the strongest inhibition of serotonin-stimulated GTP binding and specific binding of the hormone with membranes, and their effect was observed at a concentration of 10−6 M. Thus, in contrast to polycationic peptides that have no homology with signal proteins, the polycationic peptides and SR derivatives selectively affected the functional state of the AC system regulated by serotonin in the rat brain and transmission of hormonal signals.