COMPARATIVE STUDY OF MOLECULAR MECHANISMS OF NATURAL AND SYNTHETIC POLYCATIONIC PEPTIDES ACTION ON THE ACTIVITY OF
THE ADENYLYL CYCLASE SIGNALING SYSTEM
A. O. Shpakov,1 I. A. Guryanov,2 L. A. Kuznetsova,1
S. A. Plesneva,1
E. T. Zakharova,3 G. P. Vlasov,2 M. N. Pertseva 1
1 I. M. Sechenov Institute of Evolutionary Physiology and Biochemistry RAS,
2 Institute of Macromolecular Compounds RAS, and 3 Institute of Experimental Medicine RAMS,
St. Petersburg;
e-mail: alex_shpakov@list.ru
The molecular mechanisms of action of natural and synthetic polycationic peptides, forming amphiphilic helices,
on the heterotrimeric G-proteins and enzyme adenylyl cyclase (AC), components of hormone-sensitive AC system, were
studied. It is shown that synthetic peptides C-aAhx-WKK(C10)-KKK(C10)-KKKK(C10)-YKK(C10)-KK (peptide I) and
(GRGDSGRKKRRQRRRPPQ)2-K-aAhx-C(Acm)(peptide II) in dose-dependent manner stimulate the basal AC activity, inhibit
forskolin-stimulated AC activity and decrease both stimulating and inhibiting AC effects of the hormones in the
tissues (brain striatum, heart muscle) of rat and in smooth muscles of the mollusc Anodonta cygnea. AC effects of
these peptides are decreased after membrane treatment by cholera and pertussis toxins and are inhibited in the
presence of the peptides, corresponding to C-terminal regions 385-394 as- and 346-355 ai2-subunits of G-proteins.
These data give evidence that the peptides I and II act on the signaling pathways which are realized through Gs- and
Gi-proteins. At the same time, natural polycationic peptide mastoparan acts on AC system through Gi-proteins and
blocks hormonal signals mediated via Gi-proteins only. Consequently, the action of mastoparan on G-proteins is
selective and differs from the action of the synthetic peptides. It is also shown that peptide II, with branched
structure, directly interacts not only with G-proteins (less effective in comparison with peptide I with hydrophobic
radicals and mastoparan), but also with enzyme AC, the catalytic component of AC system. On the basis of data
obtained the following conclusions were made: 1) the formation of amphiphilic helices is not enough for selective
activation of G-protein by polycationic peptides, and 2) the primary structure of the peptides, the distribution of
positive charged amino acids and hydrophobic radicals in them are very important for selective interaction between
polycationic peptides and G-proteins.
Key words: adenylyl cyclase, bacterial toxin, GTP-binding protein, mastoparan, polycationic peptide,
heart muscle, C-terminal peptide, brain striatum
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