PEPTIDE 612–627 OF THYROTROPIN RECEPTOR AND ITS MODIFIED DERIVATIVES
AS THE REGULATORS OF ADENYLYL CYCLASE IN THE RAT THYROID GLAND
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
The regulation of the specific activity of the thyroid gland is carried by thyroid-stimulating hormone (TSH)
through TSH receptor (TSHR). This receptor is coupled to different types of G-proteins, including the Gs-proteins,
through which TSH stimulates the enzyme adenylyl cyclase (AC). As the application of TSH in medicine is
limited, the development of selective regulators of TSHR with agonistic and antagonistic activity is carried out.
One of the approaches to their creation is to develop the peptides corresponding to functionally important regions
of TSHR which are located in its intracellular loops (ICL) and are involved in the binding and activation of
G-proteins. We have synthesized peptide corresponding to the C-terminal region 612–627 of the third ICL of
TSHR and its derivatives modified by palmitic acid residue (at the N- or the C-terminus) or by polylysine dendrimer
(at the N-terminus), and studied their effect on the basal and TSH-stimulated AC activity in the membrane
fraction isolated from the rat thyroid. The most active was peptide 612–627-K(Pal)A modified by palmitate
at the C-terminus, where in TSHR the hydrophobic transmembrane region is located. At the micromolar concentrations
the peptide increased AC activity and reduced the AC stimulating effect of TSH. The action of the
612–627-K(Pal)A has been directed onto TSHR homologous to it, as indicated by the following facts: 1) the
inhibition of Gs-protein, the downstream component of AC system, by treating the membranes with cholera toxin
led to the blocking of peptide AC effect, 2) this effect was not detected in the tissues where no TSHR, 3) the
peptide did not significantly affect the AC stimulating effects of hormones acting via other receptors. The unmodified
peptide and the peptide with N-terminal dendrimer are far behind the 612–627-K(Pal)A in their ability
to activate AC in the thyroid, while the peptide modified by palmitate at the N-terminus was inactive. At
the same time, the peptide modified by dendrimer was comparable to the 612–627-K(Pal)A in the ability to inhibit
the AC effect of TSH, but, although to a lesser extent that it decreased the AC effects of other hormones,
demonstrating the low receptor specificity. Thus, these data point to the high efficiency of peptide
612–627-K(Pal)A, as a regulator of TSHR, and the prospects of creating the drugs based on it to control the
thyroid functions in pathology.
Key words: thyroid-stimulating hormone, thyroid-stimulating hormone receptor, the third cytoplasmic
loop, peptide, adenylyl cyclase, heterotrimeric G-protein, the thyroid gland
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