Peptides, the derivatives of intracellular regions of G protein-coupled receptors (GPCRs), are able to regulate the activity of hormonal signaling systems, acting as agonists and antagonists of the cognate receptor. The modification of GPCR-peptides by hydrophobic radicals significantly increases their biological activity. However, despite a significant progress in the development of GPCR-peptides modified by hydrophobic radical, referred to as pepducins, the impact of the localization, the hydrophobicity and the number of hydrophobic radicals involved in peptide activity has been scarcely studied. The aim of this work is a comparative study of the influence of peptide 562–572 corresponding to the C-terminal region of the third intracellular loop of rat luteinizing hormone (LH) receptor and its acylated analogs modified by palmitate and decanoate at the N- or C-terminus, or at both termini, on the functional activity of gonadotropin-sensitive adenylate cyclase (AC) system in the rat testicular membranes. We showed that peptides modified by acyl radicals at the C-terminus, where in full-size LH receptor the sixth transmembrane region is located, stimulated in a dose-dependent manner the basal AC activity and GppNHp binding capacity of Gs protein and reduced their activation by human chorionic gonadotropin. The C-palmitoylated peptide was much more active than its decanoyl counterpart, and the action exerted on AC system was tissue and receptor specific. The N-acylated peptides were not active as regulators of the AC system, but slightly affected the gonadotropin-induced signal transduction via AC system. Along with this, peptides modified by decanoyl at the C- and N-termini non-selectively decreased, but not very much, the AC inhibitory effects of different hormones. The data obtained support the hypothesis that the hydrophobic radical in GPCR-peptide mimics the transmembrane region and must be comparable with it in the size and hydrophobicity. The establishment of the criteria of modification of GPCR-peptides with hydrophobic radicals is one of the most promising ways to create drugs capable of controlling the biochemical and physiological processes in vivo.
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