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PLoS One
2011 Apr 01;64:e19384. doi: 10.1371/journal.pone.0019384.
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Origin of secretin receptor precedes the advent of tetrapoda: evidence on the separated origins of secretin and orexin.
Tam JK
,
Lau KW
,
Lee LT
,
Chu JY
,
Ng KM
,
Fournier A
,
Vaudry H
,
Chow BK
.
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At present, secretin and its receptor have only been identified in mammals, and the origin of this ligand-receptor pair in early vertebrates is unclear. In addition, the elusive similarities of secretin and orexin in terms of both structures and functions suggest a common ancestral origin early in the vertebrate lineage. In this article, with the cloning and functional characterization of secretin receptors from lungfish and X. laevis as well as frog (X. laevis and Rana rugulosa) secretins, we provide evidence that the secretin ligand-receptor pair has already diverged and become highly specific by the emergence of tetrapods. The secretin receptor-like sequence cloned from lungfish indicates that the secretin receptor was descended from a VPAC-like receptor prior the advent of sarcopterygians. To clarify the controversial relationship of secretin and orexin, orexin type-2 receptor was cloned from X. laevis. We demonstrated that, in frog, secretin and orexin could activate their mutual receptors, indicating their coordinated complementary role in mediating physiological processes in non-mammalian vertebrates. However, among the peptides in the secretin/glucagon superfamily, secretin was found to be the only peptide that could activate the orexin receptor. We therefore hypothesize that secretin and orexin are of different ancestral origins early in the vertebrate lineage.
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21559418
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Figure 1. Analyses of secretin receptor phylogeny and in silico genomic locations.(A) Receptor phylogeny: phylogenetic analysis of vertebrate receptors in Class II B1 GPCR. The tree was generated by Maximum Likelihood (ML) and plotted by MEGA 5.0. Receptors cloned in the present study are marked by an asterisk. Diverged from the ancestral VPAC-like receptor (denoted by a black dot), the P. dolloi SCTR retained the VIP/PACAP functions (branch in dotted line); whereas the X. laevis and mammalian SCTRs acquired the specificity towards secretin (branch in thick solid black line). PTHR, parathyroid hormone receptor; SCTR, secretin receptor; PAC1, pituitary adenylate cyclase-activating polypeptide (PACAP) receptor type I; VPAC1, vasoactive intestinal peptide (VIP)-PACAP receptor I; VPAC2, VIP-PACAP receptor II. (B) Chromosomal locations of secretin receptor in various vertebrate species. Genes adjacent to secretin receptor in different vertebrate genomes are shown. Homologous genes present in different species are linked to show their similarities in chromosomal location.
Figure 2. Analyses of secretin phylogeny and in silico genomic locations.(A) Ligand Phylogeny: phylogenetic analysis of the secretin/glucagon hormone precursor superfamily. The tree was generated by Maximum Likelihood (ML) and plotted by MEGA 5.0. Sequences determined in the present study are marked by an asterisk. SCT, secretin precursor; preproGHRH, prepro-growth hormone-releasing hormone; PHI-VIP, peptide histidine isoleucine-vasoactive intestinal peptide precursor; PRP-PACAP, pituitary adenylate cyclase-activating polypeptide (PACAP)-related peptide-PACAP precursor. (B) Chromosomal locations of secretin genes in various vertebrate species. Neighboring genes of secretin in different vertebrate genomes are shown. Homologous genes in proximity of secretin are linked by straight lines to demonstrate the syntenic gene environment of secretin in the analyzed vertebrate species.
Figure 3. Functional characterization of lfSCTR and xSCTR.Intracellular cAMP accumulation ([cAMP]i) in response to 100 nM of the secretin and related peptides on CHO-K1 cells transfected with (A) lfSCTR and (B) xSCTR (*** indicates P<0.001). Effects of graded concentrations of peptides on (C) lfSCTR- and (D) xSCTR-expressing cells. Peptide species: h, human; x, X. laevis, zf, zebrafish Danio rerio; gf, goldfish Carassius auratus. Values represent mean ± SEM (nâ=â4). Effects of secretin and related peptides on intracellular calcium mobilization ([Ca2+]i) in recombinant CHO cells expressing (E) lfSCTR and (F) xSCTR. Transiently transfected cells expressing the receptors were stimulated with graded concentrations of peptides. Data were expressed in ÎRFU value (maximum changes in the fluorescence signals from baseline) and converted to percentage of the maximum of xSCT-induced [Ca2+]i elevation. Results are expressed as mean ± SEM from at least 10 independent experiments, cell numberâ=â20 to 50.
Figure 4. Tissue expression profile of xSCT, lfSCTR and xSCTR.Using real-time RT-PCR, the tissue distribution patterns of lfSCTR, xSCT and xSCTR were investigated on P. dolloi and X. laevis. The expression level of each gene was calculated from respective standard curve. Data are expressed as mean ± SEM (nâ=â4).
Figure 5. Effects of xSCT on cAMP production in primary culture of R. rugulosa pancreatic ductal cells.Graded concentrations of xSCT dose-dependently stimulated the [cAMP]i in cultured pancreatic ductal cells. Forskolin was used in each experiment as a positive control to show the viability of the pancreatic ductal cells. Data are expressed as mean ± SEM (nâ=â4, *** indicates P<0.001).
Figure 6. Effects of X. laevis secretin and orexin peptides on [Ca2+]i in xOX2R-CHO cells.Data are expressed as ÎRFU value (maximum changes in the fluorescence signals from baseline) and converted to percentage of maximum xSCT-induced [Ca2+]i increase. Results are expressed as mean ± SEM from 10 independent experiments, cell numberâ=â20 to 50.
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