Tsukasa Sugo

Intracerebroventricular administration of urotensin II promotes anxiogenic-like behaviors in rodents

We identified urotensin II (U-II) as the endogenous ligand for the orphan G-protein-coupled receptor GPR14 or SENR. Both U-II and GPR14 are expressed not only in peripheral tissues but also in the brain of rodents, suggesting that U-II plays a physiological role in the central nervous system. In the present study, we investigated the central effects of U-II in rodents. Intracerebroventricular administration of U-II induced anxiogenic-like behaviors in the elevated plus maze test and the hole-board test in mice in a dose-dependent manner, as did corticotropin releasing factor (CRF). The effective doses of U-II were 10-100-fold higher than these of CRF in these tests. Our results suggest that U-II is a candidate for the mediator of some aspect of stress or anxiety in the central nervous system.

Another ligand fishing for G protein-coupled receptor 14 Discovery of urotensin II-related peptide in the rat brain

Urotensin II (UII), which was originally isolated from the teleost urophysis, was identified as an endogenous ligand for orphan G protein-coupled receptor 14 (GPR14). The structure of mammalian UII was confirmed by isolation from spinal cord in porcine, or was easily predicted from the sequence of prepro-UII in human. For rat and mouse, however, only the tentative sequences of UII peptides have been demonstrated because the typical processing sites are absent from the amino-terminal region of the mature peptides. Isolation of UII-like immunoreactivity in rat brain revealed the presence of a novel peptide, designated urotensin II-related peptide (URP). URP binds and activates the human and rat urotensin II receptors (GPR14) and has a hypotensive effect when administrated to anesthetized rats. Based on the DNA sequences of the cloned prepro-URP gene, the amino acid sequences of mature URP for mouse and human are identical to that for rat URP. These results suggest that URP is the endogenous and functional ligand for urotensin II receptor in the rat and mouse, and possibly in the human.

Antagonist activity of [Thr18,γ-methylleucine19]endothelin-1 in human endothelin receptors

Abstract Receptor binding and antagonist properties of endothelin-1 analogues, [Thr18,γ-methylleucine19]endothelin-1, [Thr18,Leu19]endothelin-1 and [Thr18,cyclohexylalanine19]endothelin-1, were investigated using cloned human endothelin ETA and ETB receptors expressed in Chinese hamster ovary cells. Among them, [Thr18,γ-methylleucine19]endothelin-1 had a high affinity for endothelin ETA and ETB receptors with respective Kd values of 300 and 110 pM and had no agonist activity on the stimulation of arachidonic acid release in endothelin ETA and ETB receptor-expressing cells. [Thr18,γ-methylleucine19]Endothelin-1 had potent antagonist activity in endothelin-1-induced arachidonic acid release in endothelin ETA and ETB receptor-expressing cells with respective pA2 values of 8.2 and 8.5. In an inositol phosphates accumulation assay, [Thr18,γ-methylleucine19]endothelin-1 also exhibited potent antagonist activity for endothelin ETA and ETB receptors with respective pA2 values of 8.0 and 8.4. In conclusion, [Thr18,γ-methylleucine19]endothelin-1 acts as a potent and nonselective antagonist with no agonist activity for cloned human endothelin ETA and ETB receptors.