Neuropeptides and their Receptors: Evolution


Multiple forms of neuropeptides and their receptors have evolved through the processes of genome duplication, gene duplication and point mutation. Some vertebrate peptide lineages have traceable origins in invertebrates, and linkage to homeobox genes may be useful in determining the lineage.

Keywords: neuropeptides; evolution of neuropeptides; evolution of G‐protein coupled receptors; G‐protein coupled receptors; Hox genes

Figure 1.

Evolutionary relationships and Hox clusters among vertebrates. The number of clusters (HC) is given beneath the name of the group. Names of classes are given in bold. Classification and time scale is based on Young .

Figure 2.

Schematic diagram of the putative evolution of the GRF superfamily of neuropeptides. Anc, ancestral gene; GRF, ancestral GRF gene; GRF, growth hormone releasing factor; PAC, pituitary adenylate cyclase activating polypeptide; Glu, glucagon; GLP, glucagon‐like peptide; PHI, peptide histidine isoleucine; VIP, vasoactive intestinal polypeptide; Sec, secretin; PRP, PACAP‐related peptide; GD, gene duplication; EDTI, exon duplication and tandem insertion and EL, exon loss.

Figure 3.

Schematic diagram of the evolution of vertebrate oxytocin/vasopressin family genes. Relationships are based on known peptide sequences, chromosomal deoxyribonucleic acid (cDNA) sequences and phylogenetic relationships. VT, vasotocin; IT, isotocin; MT, mesotocin; AVP, Arg8‐vasopressin; LVP, Lys8‐vasopressin; XT, aspargtocin, asvatocin, glumitocin, phasvatocin, seritocin or valitocin and OT, oxytocin. The dashed boxes around the elasmobranch and marsupial genes indicate regions of rapid evolution, and not all homologues are indicated.

Figure 4.

Relationships between diverse ligands and their cognate receptors. (a) Neuropeptide ligands. The unrooted tree shows relationships between a group of ligands, using nearest‐neighbour analysis (calculated using ClustalX 1.81 and drawn using NJPLOT). Invertebrate ligands are italicized. NPF, neuropeptide; F, invertebrate homologue of neuropeptide Y and conopressin is (Ile2,Ile3,Arg4)‐vasopressin, isolated from a gastropod mollusk. (b) Neuropeptide receptors. The rooted tree shows the relationships among receptors for the ligands shown in (a). Invertebrate receptors are italicized. Drm NY,Drosophila melanogaster neuropeptide Y receptor (the putative receptor for NPF). The dendrogram was based on data obtained from the G‐Protein‐Coupled Receptor Database.



Eriksson H, Berglund MM, Holmberg SK et al. (1998) The cloned guinea pig pancreatic polypeptide receptor Y4 resembles more the human Y4 than does the rat Y4. Regulatory Peptides 75: 29–37.

Herzog H, Hort Y, Schneider R and Shine J (1995) Seminalplasmin: recent evolution of another member of the neuropeptide Y gene family. Proceedings of the National Academy of Sciences of the USA 92: 594–598.

Hyodo S, Kato Y, Ono M and Urano A (1991) Cloning and sequence analyses of cDNAs encoding vasotocin and isotocin precursors of the chum salmon, Onchorhyncus keta: evolutionary relationships of neurohypophysial hormones. Journal of Comparative Physiology 160(suppl. B): 601–608.

Irwin DM, Huner O and Youson JH (1999) Lamprey proglucagon and the origin of glucagon‐like peptides. Molecular Biology and Evolution 16: 1548–1557.

McRory J and Sherwood NM (1997) Two protochordate genes encode pituitary adenylate cyclase‐activating polypeptide and related family members. Endocrinology 138: 2380–2390.

Moghadam HK, Ferguson MM and Danzmann RG (2005) Evolution of Hox clusters in Salmonidae: a comparative analysis between Atlantic salmon (Salmo salar) and rainbow trout (Oncorhynchus mykiss). Journal of Molecular Evolution 61: 636–645.

Nathans J, Thomas D and Hogness DS (1986) Molecular genetics of human color vision: the genes encoding blue, red and green pigments. Science 232: 193–202.

Prince V (2002) The Hox paradox: more complex(es) than imagined. Developmental Biology 249: 1–15.

Soderberg C, Wraith A, Ringvall M et al. (2000) Zebrafish genes for neuropeptide Y and peptide YY reveal origin by chromosome duplication from an ancestral gene linked to the homeobox cluster. Journal of Neurochemistry 75: 908–918.

Stadler PF, Fried C, Prohaska SJ et al. (2004) Evidence for independent Hox gene duplications in the hagfish lineage: a PCR‐based gene inventory of Eptatretus stoutii. Molecular Phylogenetics and Evolution 32: 686–694.

Urano A, Kato S and Suzuki M (1992) Molecular evolution of neurohypophysial hormone precursors. Progress in Brain Research 92: 39–46.

Venkatesh B, Kirkness EF, Loh Y‐H et al. (2007) Survey sequencing and comparative analysis of the elephant shark (Callorhinchus milii) genome. PLoS Biology 5: 0932–0944.

Young JZ (1978) The Life of Vertebrates, 2nd edn. Oxford, UK: Oxford University Press.

Further Reading

Cerda‐Reverter JM and Larhammar D (2000) Neuropeptide Y family of peptides: structure, anatomical expression, function, and molecular evolution. Biochemistry and Cell Biology 78: 371–392.

Danielson PB and Dores RM (1999) Molecular evolution of the opioid/orphanin gene family. General and Comparative Endocrinology 113: 169–186.

Hoegg S and Meyer A (2005) Hox clusters as models for vertebrate genome evolution. Trends in Genetics 21: 421–424.

Holmgren S and Jensen J (2001) Evolution of vertebrate neuropeptides. Brain Research Bulletin 55: 723–735.

Hoyle CHV (1996) Neuropeptides: Essential Data. Chichester, UK: Wiley.

Hoyle CHV (1998) Neuropeptide families: evolutionary perspectives. Regulatory Peptides 73: 1–33.

Hoyle CHV (1999) Neuropeptide families and their receptors: evolutionary perspectives. Brain Research 848: 1–25.

Hoyle CH, Hill J, Sanger GJ and Andrews PL (2003) Analysis of pancreatic polypeptide cDNA from the house musk shrew, Suncus murinus, suggests a phylogenetically closer relationship with humans than for other small laboratory animal species. Regulatory Peptides 114: 137–144.

Larhammar D, Wraith A, Berglund MM, Holmberg SK and Lundell I (2001) Origins of the many NPY‐family receptors in mammals. Peptides 22: 295–307.

Wraith A, Tornsten A, Chardon P et al. (2000) Evolution of the neuropeptide Y receptor family: gene and chromosome duplications deduced from the cloning and mapping of the five receptor subtype genes in pig. Genome Research 10: 302–310.

Web Links

G‐Protein‐Coupled Receptor Database. An information system for G protein‐coupled receptors, June 2006 release (10.0)


Contact Editor close
Submit a note to the editor about this article by filling in the form below.

* Required Field

How to Cite close
Hoyle, Charles HV(Mar 2008) Neuropeptides and their Receptors: Evolution. In: eLS. John Wiley & Sons Ltd, Chichester. [doi: 10.1002/9780470015902.a0006150.pub2]