MODULATION OF APOPTOSIS IN MONONUCLEAR CELLS WITH DIFFERENT VARIANTS
OF POLYMORPHISM C-262T IN CATALASE GENE
A.O. Shpakov,1,* E.A. Shpakova,2 I.I. Tarasenko,2 K.V. Derkach 1
1 I.M. Sechenov Institute of Evolutionary Physiology and Biochemistry RAS
and 2 Institute of Macromolecular Compounds RAS, St. Petersburg;
* e-mail: alex_shpakov@list.ru
Melanocortin receptors of the type 4 (M4R) play a key role in the regulation of feeding behavior, neuroendocrine
functions, and energy metabolism. The alterations in their functional activity induce obesity, metabolic
syndrome, depression, and mental disorders, which makes the search of selective regulators of M4R to be one of
the actual problems of molecular endocrinology. Promising for the development of such regulators is to design
peptides corresponding to functionally important regions of M4R. The purpose of this study was to study the influence
of synthesized N-palmitoylated peptide Palm-Thr-Gly-Thr-Ile-Arg-Gln-Gly-Ala-Asn-(Nle)-Lys-Gly-
Ala-Ile232—245-amide (Palm-232—245) structurally corresponding to the C-terminal half of the third intracellular
loop (ICL-3) of rat M4R on functional activity of adenylyl cyclase signaling system (ACSS) in the fractions
of synaptosomal membranes isolated from the brains of male rats. It has been shown that, at a concentration of
10–7 M and higher, Palm-232—245 stimulates the basal activity of adenylyl cyclase (AC) in the synaptosomal
membranes and increases the basal level of GTP binding with the EC50 values of 71 and 267 nM, respectively.
Under the combined action of low concentrations of the peptide (10–7—10–6 M) and M4R agonists, α-melanocyte-
stimulating hormone (α-MSH) and THIQ (10–7 M), we observed an additivi stimulatory effect on AC,
which disappeared when the peptide concentration was increased to 10–4—10–3 M. In the synaptosomal membranes
preincubated with 10–5 M peptide, the maximum stimulatory effect of M4R agonists on AC activity was
lower than that in controls, and EC50 values for this effect, on the contrary, increased. In the case of combined
action of the peptide and hormones (γ-MSH, serotonin, PACAP-38) that activate AC via the other receptors, the
additivity of their stimulating effects on the ACSS persisted throughout the range of peptide concentrations.
The effect of the peptide was not observed in myocardial and testicular membranes no in which there is M4R
homologous to the peptide. Thus, N-palmitoylated peptide Palm-232—245 specifically activates the ACSS in
the rat brain by acting as intracellular M4R agonist. This may be used to create drugs regulating brain melanocortin
system and physiological processes that depend on it.
Key words: adenylyl cyclase, agonist, heterotrimeric G-protein,
melanocortin receptor, melanocyte-stimulating hormone, brain, peptide, third cytoplasmic loop
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