Abstract:The neuropeptide Y (NPY) family receptors and peptides have previously been characterized in several tetrapods, teleost fishes, and in a holocephalan cartilaginous fish. This has shown that the ancestral NPY system in the jawed vertebrates consisted of the peptides NPY and peptide YY (PYY) and seven G-protein-coupled receptors named Y1–Y8 (Y3 does not exist). The different vertebrate lineages have subsequently lost or gained a few receptor genes. For instance, the human genome has lost three of the seven recep… Show more
“…Note that Y1 and Y5 are indeed located close to each other in the elephant shark as reported in the present study (see Fig. 4), like in the coelacanth Latimeria chalumnae (Larhammar and Bergqvist, 2013). Y1, Y2 and Y5 are syntenic in chicken as are Y6 and Y7, supporting the scenario shown (Bromee et al, 2006). we have found lamprey Y1.…”
Section: Introductionsupporting
confidence: 92%
“…Due to the uncertainty inherent in sequencebased phylogenetic analyses between lampreys and gnathostomes, we also compared synteny. Because the new lamprey gene is located close to Y5, like Y1 is in gnathostomes, we conclude that (Larsson et al, 2009;Larhammar and Bergqvist, 2013). Human Y6 is a pseudogene as indicated by orange color.…”
Section: Introductionmentioning
confidence: 92%
“…It was found to be located on the same scaffold as the ortholog of the Y5 sequence that we recently characterized in P. marinus (Xu et al, 2013) (see below). As only a single Y5 gene has been found in all vertebrate genomes so far analyzed (Larhammar and Bergqvist, 2013;Larsson et al, 2009), we assume that these are orthologous to each other. From this follows that the neighboring Y1-subfamily sequence located adjacently should be orthologous to Y1.…”
Section: Sequence and Phylogenetic Analysesmentioning
confidence: 99%
“…After the loss of some of the duplicates, seven NPY-family receptors remained ( Fig. 1) when the classes of gnathostomes began to diverge from one another, and all seven subtypes have been found in representatives for cartilaginous fishes (Larsson et al, 2009), lobe-finned fishes (Larhammar and Bergqvist, 2013) and ray-finned fishes (unpublished). These seven receptor subtypes can be grouped into three subfamilies based on their ancestry and sequence similarity: the Y1 subfamily (with members Y1, Y4, Y6, Y8), the Y2 subfamily (Y2, Y7) and the Y5 (alone) subfamily.…”
Section: Introductionmentioning
confidence: 95%
“…Later PP (pancreatic polypeptide) appeared in the early lobe-finned lineage as a copy of PYY (Larhammar and Bergqvist, 2013). Duplicates of both NPY and PYY arose in the teleost fish ancestor as a result of another tetraploidization named 3R (Jaillon et al, 2004) and these genes are therefore named NPYa, NPYb, PYYa and PYYb .…”
“…Note that Y1 and Y5 are indeed located close to each other in the elephant shark as reported in the present study (see Fig. 4), like in the coelacanth Latimeria chalumnae (Larhammar and Bergqvist, 2013). Y1, Y2 and Y5 are syntenic in chicken as are Y6 and Y7, supporting the scenario shown (Bromee et al, 2006). we have found lamprey Y1.…”
Section: Introductionsupporting
confidence: 92%
“…Due to the uncertainty inherent in sequencebased phylogenetic analyses between lampreys and gnathostomes, we also compared synteny. Because the new lamprey gene is located close to Y5, like Y1 is in gnathostomes, we conclude that (Larsson et al, 2009;Larhammar and Bergqvist, 2013). Human Y6 is a pseudogene as indicated by orange color.…”
Section: Introductionmentioning
confidence: 92%
“…It was found to be located on the same scaffold as the ortholog of the Y5 sequence that we recently characterized in P. marinus (Xu et al, 2013) (see below). As only a single Y5 gene has been found in all vertebrate genomes so far analyzed (Larhammar and Bergqvist, 2013;Larsson et al, 2009), we assume that these are orthologous to each other. From this follows that the neighboring Y1-subfamily sequence located adjacently should be orthologous to Y1.…”
Section: Sequence and Phylogenetic Analysesmentioning
confidence: 99%
“…After the loss of some of the duplicates, seven NPY-family receptors remained ( Fig. 1) when the classes of gnathostomes began to diverge from one another, and all seven subtypes have been found in representatives for cartilaginous fishes (Larsson et al, 2009), lobe-finned fishes (Larhammar and Bergqvist, 2013) and ray-finned fishes (unpublished). These seven receptor subtypes can be grouped into three subfamilies based on their ancestry and sequence similarity: the Y1 subfamily (with members Y1, Y4, Y6, Y8), the Y2 subfamily (Y2, Y7) and the Y5 (alone) subfamily.…”
Section: Introductionmentioning
confidence: 95%
“…Later PP (pancreatic polypeptide) appeared in the early lobe-finned lineage as a copy of PYY (Larhammar and Bergqvist, 2013). Duplicates of both NPY and PYY arose in the teleost fish ancestor as a result of another tetraploidization named 3R (Jaillon et al, 2004) and these genes are therefore named NPYa, NPYb, PYYa and PYYb .…”
Neuropeptide Y (NPY), a 36‐amino‐acid peptide, functions as a neurotransmitter in both the central and peripheral nervous systems by activating the NPY receptor subfamily. Notably, NPY analogs display varying selectivity and exert diverse physiological effects through their interactions with this receptor family. [Pro34]–NPY and [Leu31, Pro34]–NPY, mainly acting on Y1R, reportedly increases blood pressure and postsynaptically potentiates the effect of other vasoactive substances above all, while N‐terminal cleaved NPY variants in human body primary mediates angiogenesis and neurotransmitter release inhibition through Y2R. However, the recognition mechanisms of Y1R and Y2R with specific agonists remain elusive, thereby hindering subtype receptor‐selective drug development. In this study, we report three cryo‐electron microscopy (cryo‐EM) structures of Gi2‐coupled Y1R and Y2R in complexes with NPY, as well as Y1R bound to a selective agonist [Leu31, Pro34]–NPY. Combined with cell‐based assays, our study not only reveals the conserved peptide‐binding mode of NPY receptors but also identifies an additional sub‐pocket that confers ligand selectivity. Moreover, our analysis of Y1R evolutionary dynamics suggests that this sub‐pocket has undergone functional adaptive evolution across different species. Collectively, our findings shed light on the molecular underpinnings of neuropeptide recognition and receptor activation, and they present a promising avenue for the design of selective drugs targeting the NPY receptor family.
As one of the most important multifunctional peptides, neuropeptide Y (NPY) performs its physiological functions through different subtype receptors. In this study, full-length cDNAs of two NPY receptors (YRs) in orange-spotted grouper (Epinephelus coioides) were cloned and named npy8br (y8b) and npy2r (y2). Phylogenetic analysis indicated that the Y8b receptor is an ortholog of the teleostean Y8b receptor, which belongs to the Y1 subfamily, and the Y2 receptor is an ortholog of the teleostean Y2 receptor, which belongs to the Y2 subfamily. Both of the YRs have G protein-coupled receptor family profiles. Multiple alignments demonstrate that the extracellular loop regions of YRs have distinctive residues of each species. Expression profile analysis revealed that the grouper Y8b receptor mRNA is primarily expressed in the brain, stomach and intestine, while the grouper Y2 receptor mRNA is primarily expressed in the brain, ovary, liver and heart. Double immunofluorescence analysis determined that the grouper YRs interact with the grouper NPY around the human embryonic kidney 293T cell surface. Furthermore, site-directed mutagenesis in a phage display system revealed that Asp(6.59) might be a common NPY-binding site, while Asp(2.68) of the Y8b receptor and Glu(5.24) of the Y2 receptor could be likely involved in subtype-specific binding. Combining the expression profile and ligand-binding feature, the grouper Y8b receptor could be involved in regulating food intake via the brain-gut axis and the grouper Y2 receptor might play a role in balancing the regulatory activity of the Y8b receptor and participate in metabolism in the liver and ovary.
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