REGULATION OF ADENYLYL CYCLASE ACTIVITY IN THE RAT TESTES BY ACYLATED DERIVATIVES OF PEPTIDE 562—572 OF
LUTEINIZING HORMONE RECEPTOR
E.A. Shpakova,1 A.O. Shpakov 2
1 Institute of Macromolecular Compounds RAS and 2 I.M. Sechenov Institute of Evolutionary Physiology
and Biochemistry RAS, St. Petersburg;
2 e-mail: alex_shpakov@list.ru
One of directions of the search of hormonal signaling systems regulators is the development of peptides
that correspond to the cytoplasmic regions of G-protein-coupled receptors (GPCR). Modification of the peptides
with hydrophobic radicals increases their efficiency and selectivity. But currently is not studied as the activity
of the peptide depends on the localization of the hydrophobic radicals, their number and the chemical nature.
The aim of this work was the synthesis of modified by fatty acid radicals derivatives of peptide 562—572
corresponding to the C-terminal region of luteinizing hormone receptor (LHR), and the study of regulatory effects
of the acylated LHR-peptides on the basal and hormone-stimulated activity of adenylyl cyclase (AC) in
the rat tissues. To elucidate the effect of localization of hydrophobic radicals and their number the modification
of peptide 562—572 only at the N- or C-terminus or at both ends was carried out. To study the effect of hydrophobicity
the residues of palmitic (Pal) and decanoic (Dec) acids were selected. Using a solid phase strategy we
have synthesized unmodified peptide NDTKIAKK-Nle-A562—572-KA (1) and five of its acylated analogues,
such as N[K(Dec)]DTKIAKK-Nle-A562—572-KA (2), NKDTKIAKK-Nle-A562—572-[K(Dec)]A (3), N[K(Dec)]
DTKIAKK-Nle-A562—572-[K(Dec)]A (4), N[K(Pal)]DTKIAKK-Nle-A562—572-KA (5), and NKDTKIAKK-Nle-
A562—572-[K(Pal)]A (6). Peptide 6 modified with palmitate at the C-terminus to a large extent increased the basal
AC activity and reduced AC stimulating effect of human chorionic gonadotropin (hCG) in the testes of rats,
peptides 3 and 4 modified with decanoate at the C-terminus were less effective, but exceeded in activity the unmodified
peptide 1, while peptides 2 and 5 acylated at the N-terminus were little active. The action of peptides
was characterized by the tissue and the receptor specificity. Thus, the modification of LHR-peptide 562—572
with fatty acid radicals at the C-terminus increases its regulatory effect on the functional activity of the adenylate
cyclase system in the rat testes, indicating promising the modification of GPCR-peptides with hydrophobic
radicals. These data support the hypothesis that the hydrophobic radical to be localized in the locus of
GPCR-peptide, where a transmembrane domain is located in the receptor.
Key words: adenylyl cyclase, hydrophobic radical, gonadotropin, decanoate, palmitate, peptide, luteinizing
hormone receptor, G protein-coupled receptor
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