Evolution of vertebrate opioid receptors

Abstract

The opioid peptides and receptors have prominent roles in pain transmission and reward mechanisms in mammals. The evolution of the opioid receptors has so far been little studied, with only a few reports on species other than tetrapods. We have investigated species representing a broader range of vertebrates and found that the four opioid receptor types (delta, kappa, mu, and NOP) are present in most of the species. The gene relationships were deduced by using both phylogenetic analyses and chromosomal location relative to 20 neighboring gene families in databases of assembled genomes. The combined results show that the vertebrate opioid receptor gene family arose by quadruplication of a large chromosomal block containing at least 14 other gene families. The quadruplication seems to coincide with, and, therefore, probably resulted from, the two proposed genome duplications in early vertebrate evolution. We conclude that the quartet of opioid receptors was already present at the origin of jawed vertebrates Ϸ450 million years ago. A few additional opioid receptor gene duplications have occurred in bony fishes. Interestingly, the ancestral receptor gene duplications coincide with the origin of the four opioid peptide precursor genes. Thus, the complete vertebrate opioid system was already established in the first jawed vertebrates.chromosome ͉ G protein-coupled receptor ͉ gene duplication S everal opioid peptides, including endorphin and enkephalins, are important regulators of nociceptive neurotransmission and reward mechanisms in mammals. Specific binding sites in the brain for opioid compounds were first reported in 1973 (1-3), and it was soon evident that more than one type of binding site existed (4). Subsequently three distinct opioid receptors were identified and designated delta, kappa, and mu. These receptors were cloned and found to be encoded by separate genes belonging to the superfamily of rhodopsin-like G protein-coupled receptors (GPCRs) (5-8). The genes for the opioid receptors (OPR) have been named OPRD1 (delta), OPRK1 (kappa), and OPRM1 (mu) by the HUGO Gene Nomenclature Committee (HGNC).Homology searches resulted in the discovery of a fourth receptor in both rodents and humans initially named ORL1 for opioid receptor-like (9) or LC132 (10). This receptor shows 48-49% identity to the other three human receptors, which display 55-58% identity among one another. The receptor has been named NOP by the International Union of Basic and Clinical Pharmacology and its gene has been named OPRL1 by HGNC. An endogenous peptide ligand with some similarity to the other opioid peptides was discovered and named nociceptin (11) or orphanin FQ (12).The evolution of the endogenous opioid peptide ligands has been studied extensively and the major peptide ligands are generated from four prepropeptides that are encoded by separate genes in tetrapods. The genes arose by duplications in the common ancestor of tetrapods and bony fishes (13). Opioid receptor sequences have been reported for a few nonmammalian tetrapods (1...

Delta opioid agonists: a concise update on potential therapeutic applications

“…19 It is a 372 amino acid 7-transmembrane G protein-coupled receptor (GPCR) [20][21][22] with three extra-and three intracellular loops with the amino terminus extracellular and the carboxyl terminus intracellular. 7 More detailed structural characterization has recently been published. 23 The DOR has relatively high binding affinity for the endogenous opioids ß-endorphin and Leu-enkephalin.…”

“…5,6 One advance has been the recognition that the effects of analgesics are mediated through (opioid) receptors and that there are three major types of such receptors, originally termed l, d and j with a common evolutionary history. 7 Ligands that possess selective affinity for d-opioid receptors might, it is hoped, produce analgesia without some of the adverse effects. They might also be useful for the treatment of other conditions.…”

Mu Opioids and Their Receptors: Evolution of a Concept

“…Phylogenetic analysis suggests two rounds of genome-wide duplication (paleoploidization) from a single ancestral opioid gene (unireceptor) (Ohno, 1999;Escriva et al, 2002;Lundin et al, 2003), with the first yielding the ancestral DOR-1/MOR-1 and ORL-1/KOR-1 genes. The duplication then led to DOR-1 and MOR-1, as well as KOR-1 and ORL-1 (Dreborg et al, 2008;Larhammar et al, 2009;Stevens, 2009). The predicted MOR-1 protein sequences from 27 species reveals four major clades as follows: 1) fish, 2) amphibians, 3) birds, and 4) mammals, mimicking the evolutionary tree of life (Fig.…”

Discovery of a Novel Insect Neuropeptide Signaling System Closely Related to the Insect Adipokinetic Hormone and Corazonin Hormonal Systems

“…This again would be in agreement with a common evolutionary origin of the two hormonal systems, where some aspects of the original function of the ancestral system would have been conserved in both the oxytocin and vasopressin systems. Other examples of receptor neuropeptide ligand co-evolution are the mammalian glycoprotein hormones and their receptors (28,29) and the opioid/orphanin peptides and their receptors (30).…”