350 rub
Journal Technologies of Living Systems №2 for 2011 г.
Article in number:
NON-HORMONAL REGULATORS OF ADENYLYL CYCLASE SIGNALING SYSTEM ON THE BASIS OF PEPTIDES, DERIVATIVES OF THE THIRD INTRACELLULAR LOOP OF SEROTONIN RECEPTORS
Keywords: adenylyl cyclase heterotrimeric G protein brain peptide serotonin serotonin receptor third intracellular loop
Authors:
E.A. Shpakova, I.I. Tarasenko, K.V. Derkach, O.V. Chistyakova, G.P. Vlasov, A.O. Shpakov
Abstract:
The regions of the third intracellular loop of the majority of the serpentine type receptors are responsible for interaction with heterotrimeric G proteins. Synthetic peptides corresponding to these regions to be able to activate G proteins in the absence of hormone and to influence transduction of hormonal signal realized via cognate receptors. The aim of the work is the synthesis of the peptides, derivatives of the third intracellular loop of serotonin receptors (SRs) of the subtype 1B (SR1B) and the type 6 (SR6) coupled with G proteins of the stimulatory (Gs) and the inhibitory (Gi) types, respectively, and the study of molecular mechanisms of peptides action on serotonin-sensitive adenylyl cyclase signaling system in the brain of rats. We synthesized in the first time peptide ARERKATKTL307-316K-amide (I), derivative of С-terminal region of the third loop of human and rat SR1B/1D, and two peptides KHSRKALKASL258-268KA-amide (II) and KHSRKALKASL258-268K(Pal)A-amide (III), derivatives of С-terminal region of the third loop of rat SR6. It was shown that SR6-peptides II and III in the absence of hormone stimulated the basal adenylyl cyclase (AC) activity and increase basal level of GTP-binding in brain tissues of rats. Peptide I, derivative SR1B, stimulated GTP-binding, decreased forskolin-stimulated AC activity, but practically not influenced the basal AC activity. Stimulating AC and GTP-binding effects of serotonin and selective SR6-agonist EMD-386088 in the presence of SR6-peptides II and III were decreased, while stimulating effects of SR1/7-agonists 5-carboxamidotryptamine and 8-OH-DPAT were unchanged. In the presence of SR1B-peptide I stimulating GTP-binding effects of selective SR1B-agonist 5-nonyloxytryptamine and, in a lesser extent, corresponding effects of serotonin, 5-carboxamidotryptamine, 8-OH-DPAT and 5-methoxy-N,N-dimethyltryptamine, also acting on SR of the type 1, were decreased, while stimulating GTP-binding effect of SR6-agonist EMD-386088 in the presence of peptide I was preserved. It gives evidence in favor of SR-peptides I-III high specifically interact with cognate receptors. Similar results were obtained with selective antagonists of SRs. Thus, the peptides, derivatives of C-terminal regions of the third intracellular loop of SR1B and SR6, selectively activate G proteins and trigger cAMP-dependent signaling cascade and also disturb the transduction of serotonin signals via receptor homologous to them. These peptides are a new generation of highly selective and efficient non-hormonal regulators of serotonin-sensitive signaling systems.
Pages: 29-37
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