Chemical structures of human urotensin II (compound 1) and mammalian URP (compound 2).

Structure of the human prepro-UII and prepro-URP genes. (A) The prepro-UII gene comprises five exons and encodes two precursor isoforms (variants a and b) that only differ at their N-terminal extremity, the UII sequence being located at the C-terminal extremity. Each isoform generates the same mature UII peptide through proteolytic cleavage at a tribasic site (KKR). (B) The prepro-URP gene comprises five exons. The URP sequence is located at the C-terminal extremity of the URP precursor and the mature peptide is generated by proteolytic cleavage at a dibasic site (KR). SP, signal peptide; ATG/AUG, initiation codon; Stop, termination codon. (Adapted from Lihrmann et al., 2013.)

Schematic representation of the putative ancestral tetraparalogon bearing genes of the UII and somatostatin families. The other families displayed are as follows: ATPB1B, ATPase, Na⁺/K⁺ transporting, β polypeptide; ATP13A, ATPase type 13A; CLIC, chloride intracellular channel; DVL, dishevelled homolog 1 (Drosophila); FGF, fibroblast growth factor; MBNL, muscleblind-like splicing regulator 2; RAP2, member of RAS oncogene family; SENP, SUMO1/sentrin specific peptidase; TP, tumor protein. The gray dashed boxes represent lost genes. The color code is the same as in Fig. 3. (Adapted from Parmentier et al., 2011.)

A proposed evolutionary model for the evolution of the UII gene family. The names of the different paralogous genes are given in the boxes. Crossed-out boxes represent lost genes. R, rounds of whole-genome duplication. ? denotes genes that have not been detected, either because of incomplete genome assembly in the relevant species or because these genes have been lost during evolution. (Adapted from Tostivint et al., 2014.)

Amino acid sequences of human urotensin II (hUII), human urotensin II–related peptide and somatostatin (SST). All three peptides exhibit a disulfide bridge and a conserved Phe-Trp-Lys motif (red box).

Amino acid sequence and membrane topology of the human UII receptor. (Adapted from Kim et al., 2010, and Chatenet et al., 2013c.)

Signaling pathways associated with UT after UII or URP activation. AC, adenylyl cyclase; Akt, protein kinase B; cAMP, cyclic adenosine monophosphate; EGFR, epidermal growth factor receptor; ERK1/2, extracellular signal-reduced kinase 1/2; GSK-3β, glycogen synthase kinase-3β; JNK, c-Jun N-terminal kinase; P38, P38 mitogen-activated protein kinases; PIP₂, phosphatidylinositol 4,5-bisphosphate; PKA, protein kinase A; PKC, protein kinase C; PLA₂, phospholipase A₂; RhoA, Ras homolog gene family, member A; ROCK, Rho kinase; ROS, reactive oxygen species.

Effect of human UII on inositol phosphate turnover and intracellular calcium concentration ([Ca²⁺]_i) in human UT-transfected CHO cells. (A) In cells labeled with [³H]inositol, graded concentrations of UII, in the presence of Li block, induces a dose-dependent increase of inositol phosphate (IPx) formation. DPM, disintegrations per minute. (B) Time course effect of UII (100 nM, black bar) on [Ca²⁺]_i in Fura 2-loaded cells. In the presence of extracellular Ca²⁺, a biphasic response in observed, i.e., a peak originating from intracellular calcium stores (as a consequence of IP formation) and a plateau phase caused by an entry of extracellular Ca²⁺. In the absence of extracellular Ca²⁺, the response is monophasic with the plateau-phase missing. (C) Effect of graded concentrations of UII on the peak [Ca²⁺]_i response. [Reprinted from McDonald et al. (2007). Used with permission.]

Chemical structures of various pepditic ligands of UT. The residue(s) modified from the original scaffold are indicated in red.

Chemical structures of various nonpeptidic agonists and antagonists of the UT receptor. Compounds 17, 18, and 19 are agonists; the remaining compounds are antagonists.

[¹²⁵I]human UII binding to recombinant human UT. (A) [¹²⁵I]UII binding is presented with Scatchard analysis of the binding isotherm. Addition of a peptidase inhibitor cocktail (+PI; i.e., amastatin, bestatin, phosphoramidon, and captopril) does not affect binding. (B) Addition of an excess of unlabeled UII (dotted line) fails to induce radioligand dissociation. [Reprinted from Song et al. (2006b). Used with permission.]

A proposed evolutionary model for the UT gene family. The names of the different paralogous genes are given in the boxes. Crossed-out boxes represent lost genes. R, rounds of the whole-genome duplication. [Adapted from Tostivint et al. (2014).]

Effect of UII on locomotor activity. Mice were given intracerebroventricular injections of vehicle or graded doses of UII (10–10,000 ng/mouse) and the horizontal (A) and vertical (B) components of motor activity were measured for four consecutive periods of 10 minutes. Mean ± S.E.M. of data from 14 mice per group. Dunnett’s t test (*P < 0.005; **P < 0.01; ***P < 0.001). [Reprinted from do Rego et al. (2005). Used with permission.]

Effect of UII on anxiety-like behavior. Mice were given intracerebroventricular injections of vehicle or graded doses of UII (1–10,000 ng/mouse) and were placed at the center of an elevated plus-maze 10 minutes later. The number of entries (A), the time spent (B), and the distance traveled (C) in the open arms, in the central area, and in the closed arms of the maze were measured for 5 minutes. Mean ± S.E.M. of data from 10 to 20 mice per group. Dunnett’s t test (*P < 0.05; **P < 0.01; ***P < 0.001). [Reprinted from do Rego et al. (2005). Used with permission.]